Quinolones as serine protease inhibitors

ABSTRACT

The invention discloses quinolinones which display inhibitory effects on serine proteases such as factor Xa, thrombin and/or factor VIIa. The invention also discloses pharmaceutically acceptable salts and prodrugs of the compounds, pharmaceutically acceptable compositions comprising the compounds, their salts or prodrugs, and methods of using them a therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.

This application is a 371 of PCT/US98/26709, filed Dec. 15, 1998, whichclaims benefit of U.S. provisional Application 60/080,090 filed Mar. 31,1998.

FIELD OF THE INVENTION

In one aspect, this invention discloses quinolinones which displayinhibitory effects on serine proteases such as factor Xa, thrombin,and/or factor VIIa. The invention also discloses pharmaceuticallyacceptable salts and prodrugs of the compounds, pharmaceuticallyacceptable compositions comprising the compounds, their salts orprodrugs, and methods of using them as therapeutic agents for treatingor preventing disease states in mammals characterized by abnormalthrombosis.

BACKGROUND OF THE INVENTION

In economically developed countries, cardiovascular disease stillrepresents a major cause of mortality. In particular, abnormalcoagulation and inappropriate thrombus formation within blood vesselsprecipitates many acute cardiovascular disease states. While it has longbeen recognized that a variety of plasma proteins such as fibrinogen,serine proteases, and cellular receptors are involved in hemostasis, itis the abnormal regulation that has emerged as important contributingfactors to cardiovascular disease. Thrombin can be considered the key orprincipal regulatory enzyme in the coagulation cascade; it serves apluralistic role as both a positive and negative feedback regulator innormal hemostasis. However, in some pathologic conditions, the former isamplified through catalytic activation of cofactors required forthrombin generation such as factor Xa. Factor Xa, as part of theprothrombinase complex composed of non-enzymatic cofactor Va, calciumions and a phospholipid membrane surface regulates the generation ofthrombin from its zymogen prothrombin. Furthermore, the location of theprothrombinase complex at the convergence of both the intrinsic andextrinsic coagulation pathways suggests that inhibition of factor Xa,and hence thrombin generation, may be a viable approach to limiting theprocoagulant activity of thrombin.

Indeed, ample evidence exists for the role of factor Xa inhibitors asanticoagulants. Antistasin, a potent inhibitor of blood coagulationfactor Xa, from the Mexican leech: Haementeria officinalis, displaysantithrombotic activity in various models of arterial and venousthrombosis (Lapatto et al., Embo J., 1997:5151-61). Other protein orpolypeptide factor Xa inhibitors include recombinant tick anticoagulantpeptide (rTAP), which is known to accelerate the recombinant tissueplasminogen activator mediated clot lysis and prevent acute reocclusionin the dog, hence indicating factor Xa inhibitors may be useful as anadjunct to thrombolytic therapy (Mellott et al., Fibrinolysis,1993:195-202). Furthermore, in a canine coronary artery, electrolyticlesion model rTAP was demonstrated to reduce thrombus mass and time toocclusion in the absence of dramatic hemodynamic or hemostatic changesindicating the primary role for factor Xa in the process of arterialthrombosis (Lynch et al., Thromb. Haemostasis, 1995:640-645, Schaffer etal., Circulation, 1991:1741-1748). On the venous side, rTAP was alsodemonstrated to reduce fibrin deposition in a rabbit model of venousthrombosis while having little affect on systemic hemostatic parameters(Fioravanti et al., Thromb. Res., 1993:317-324). In addition to theserelatively high molecular weight proteins that are not suitable as oralantithrombotic agents, there also exist examples of low molecular weightfactor Xa inhibitors. In particular DX9065a, a low molecular weightsynthetic factor Xa inhibitor, has also shown antithrombotic potentialin various experimental thrombosis, rat models. In both arteriovenousshunt and venous stasis models inhibition of thrombus formation wasachieved at doses that had little effect on APTT indicating that DX9065ais effective in preventing thrombosis and hence has therapeuticantithrombotic potential (Wong et al., Thromb. Res., 1996:117-126).

The majority of factor Xa inhibitors known to date have been previouslysummarized in two reviews (Edmunds et al., Annual Reports in MedicinalChemistry, 1996:51, Kunitada and Nagahara Curr, Pharm. Des.,1996:531-542). However, it is readily apparent that there still exists aneed for more effective agents that regulate factor Xa proteolyticactivity.

Some quinolinones have been reported, and these compounds have displayedmarked pharmacological activity:

Van den Bogaert, Res. Discl., 1992;340:607-608; Qar et al., Lazdunski,Michel, Mol. Pharmacol., 1988;33(4):363-369; Japanese Patent 56125388;Japanese Patent 56049359; Great Britain Patent 1305278; German Patent2007468; Petyunin P. A., Ukr. Khim. Zh. 1971;37(1):44-46; U.S. Pat. No.3,330,823; European Patent 797376; Timari et al, Hajos, Gyorgy, Synlett(1997); Issue 9:1067-1068; World Publication 9707116; Lopez-AlvaradoPilar, J. Chem. Soc., Perkin Trans. 1, 1997;Issue 3:229-233; EuropeanPatent 334135; and European Patent 24638.

None of the above articles set forth above disclose or suggest compoundsof Formula I that are inhibitors of serine proteases involved in theblood coagulation cascade.

SUMMARY OF THE INVENTION

One object of the present invention is to provide serine proteaseinhibitors that display inhibitory activity towards enzymes involved inthe coagulation cascade and principally the target enzymes, factor Xa,thrombin, and factor VIIa.

A further object of the present invention is to provide serine proteaseinhibitors that display inhibitory activity towards the target enzymefactor Xa and are provided for in a pharmacologically acceptable state.

Still, a further object of the present invention is to provide for theuse of these factor Xa inhibitors and formulations thereof asanticoagulant and factor Xa inhibitory agents.

Yet, a further object of the present invention is to provide for the useof these factor Xa inhibitors and formulations thereof for therapeutictreatment of various thrombotic maladies.

A further object of the present invention is a process for the synthesisof these low molecular weight thrombin inhibitors. The enzyme inhibitorsof the present invention are encompassed by the structure of generalFormula I set forth below.

The present invention meets these objectives and provides for novelcompounds that display antithrombotic activity. More specifically, thepresent invention provides for novel compounds that displayantithrombotic activity via the inhibition of factor Xa as reflected inFormula I, or pharmaceutically acceptable salts or prodrug formsthereof. The present invention also provides pharmaceutically acceptablecompositions comprising the novel compounds or their salts or prodrugforms and methods of using them as therapeutic agents for treating orpreventing disease states in mammals characterized by abnormalthrombosis.

Thus, in a first embodiment, the present invention provides novelcompounds of Formula I:

or stereoisomers or pharmaceutically acceptable salts, esters, amides,or prodrugs thereof, wherein:

-   A is selected from CH₂, CH, C(alkyl);-   B is selected from H, alkyl, cycloalkyl, heteroalkyl,    cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle,    heterocycloalkyl, each optionally substituted with R₁ and R₂;-   D is selected from H, alkyl, cycloalkyl, heteroalkyl,    cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle,    heterocycloalkyl, each optionally substituted with R₁ and R₂;-   E is absent or selected from O, S, NH;-   F is selected from N, NCH₂, CH₂N;-   G is absent or selected from alkyl, alkyl interrupted by one or more    heteroatoms, cycloalkyl, cycloalkyl interrupted by one or more    heteroatoms;-   J is absent or selected from aryl or heterocycle each optionally    substituted with R₁ and R₂;-   K is absent or selected from an alkyl, alkyl interrupted by one or    more heteroatoms, cycloalkyl interrupted by one or more heteroatoms,    cycloalkylalkyl interrupted by one or more heteroatoms, each    optionally substituted with R₁ and R₂;-   L is selected from H, chlorine, fluorine, bromine, iodine, OH,    O(alkyl), amine, alkyl, fluoroalkyl, amide, NO₂, SH,    S(O)_(n)(alkyl), SO₃H, SO₃alkyl, aldehyde, ketone, acid, ester,    urea, Oalkylamide, Oalkylester, Oalkylacid, Nalkylacid, alkylamine,    alkylamide, alkylketone, alkylacid, alkylester, alkylurea,    Nalkylamide, Nalkylester, NC(═O)alkyl, NC(═O)aryl, nitrile,    NC(═O)cycloalkyl, NC(═O)cycloalkylalkyl, NC(═O) alkylaryl, R₁, R₂;-   R₁ is selected from H, amine, alkylamine, amide, C(—NH)NHNH₂,    alkylC(═NH)NHNH₂, C(═NH)NHOH, alkylC(═NH)NHOH, NHC(═NH)NH₂,    alkylNHC(═NH)NH₂, C(═S)NH₂, alkylC(═S)NH₂, C(═NH)alkyl,    alkylC(═NH)alkyl, C(═NR₃)N(R₄)(R₅), alkylC(═NR₃)N(R₄)(R₅);    -   R₂ is selected from H, chlorine, fluorine, bromine, iodine, OH,        Oalkyl, amine, alkylaldehyde, alkylamide, alkylester,        alkylketone, alkylacid, Oalkylamide, Oalkylacid, Oalkylester,        aninealkylacid, aminealkylamide, aminealkylester, NC(═O)alkyl,        NC(═O)aryl, NC(═O)cycloalkyl, NC(═O)alkylaryl, alkylamine,        amide, aldehyde, ester, ketone, NO₂, SH, S(O)_(n)(C₁₋₁₀alkyl),        SO₃H, SO₃alkyl, CHO, acid, alkyl, C(═NH)alkyl, C(═NH)NHNH₂,        alkylC(═NH)NHNH₂, C(═NH)NHOH, alkylC(═NH)NHOH, NHC(═NH)NH₂,        alkylNHC(═NH)NH₂, C(═S)NH₂, alkylC(═S)NH₂, alkylC(═NH)alkyl,        C(═NR₃)N(R₄)(R₅), alkylC(═NR₃)N(R₄)(R₅);-   R₃, R₄, and R₅ are a hydrogen atom, alkyl group having 1 to 4 carbon    atoms optionally interrupted by a heteroatom, or R₄ and R₅ are    bonded to form —(CH₂)_(p)—W—(CH₂)_(q)-, wherein p and q are an    integer of 2 or 3, a certain position on the methylene chain is    unsubstituted or substituted by a n alkyl group having 1 to 4 carbon    atoms, W is a direct bond, —CH₂—, —O—, —N(R₆)—, or —S(O)_(r) wherein    R₆ is H or alkyl, and r is 0 or 1 or 2;-   n is selected from 0, 1, 2;-   X₁ is C or N;-   X₂ is C or N;-   X₃ is C or N;-   X₄ is C or N; and    -   represents an optional additional bond.

Preferred group of compounds have the Formula II:

or stereoisomers or pharmaceutically acceptable salts, esters, amides,or prodrugs thereof, wherein B, G, H, K, L, and—are as defined above.

More preferred compounds provided by this invention are compounds ofFormula III

wherein X, Y, R₇, R₈, and—are as follows:

-   X is selected from (CH₂)₅,    -   (CH₂)₄,    -   (CH₂)₆,    -   CH₂C(═O)NHCH₂CH₂,    -   CH₂CH₂NHC(═O)CH,    -   (CH₂)₂NH(CH₂)₂,    -   (CH₂)₂O(CH₂)₂,    -   C₆H₄,    -   CH₂C₆H₄,    -   C₆R₄CH₂,    -   C₆H₁₀,    -   CH₂C₆H₁₀    -   C₆H₁₀CH₂,    -   C₅H₈,    -   CH₂C₅H₈,    -   CH₅CH₂, and    -   CH₂CH═CHCH₂CH₂;-   Y is selected from 2,6-dimethylpiperidinyl,    -   piperidinyl,    -   2,6,6-tetramethyl-piperidinyl-4-one,    -   (2-carboxy)piperidinyl,    -   (3-carboxy)piperidinyl,    -   (4-carboxy)piperidinyl,    -   3,5-dimethylpiperidinyl,    -   (4-hydroxy)piperidinyl,    -   (2-imino)piperidinyl,    -   piperidin-4-one-yl,    -   (2-dimethylaminomethyl)-piperidinyl,    -   (4-dimethylamino)-piperidinyl,    -   (4-sulphonyloxy)-piperidinyl,    -   (2-phenyl)piperidinyl, 2,5-dimethylpyrrolidinyl,    -   pyrrolidinyl,    -   (2-carboxy)pyrrolidinyl,    -   (3-N-acetyl-N-methyl)pyrrolidinyl,    -   (3-amino)pyrrolidinyl, (2,5-bis-methoxymethyl)-pyrrolidinyl,    -   2-hydroxymethyl-pyrrolidinyl,    -   2-hydroxymethyl-5-methyl-pyrrolidinyl,    -   diisopropylamino,    -   diethylamino,    -   methylamino,    -   1-methyl-4,5-dihydro-1H-imidazol-2-yl,    -   2,5-dimethyl-1H-1-imidazolyl, morpholinyl,    -   2,6-dimethylmorpholinyl,    -   piperazinyl,    -   2,6-dimethylpiperazinyl,    -   1H-pyrazolyl,    -   tetrahydro-1H-pyrazolyl,    -   2,5-dimethyltetrahydro-1H-1-pyrazolyl, and    -   1,2,3,4-tetrahydro-2-oxo-3-phenyl-1-quinolinyl;-   R₇ is selected from (3-amidino)phenyl,    -   phenyl,    -   4-methoxyphenyl,    -   4-(amidino)phenyl,    -   3-(aminocarbonyl)phenyl,    -   3-(methoxycarbonyl)phenyl,    -   (3-hydroxy)phenyl,    -   [3-hydroxylamino(imino)methyl]-phenyl,    -   [3-hydrazino(imino)methyl]-phenyl,    -   (3-aminomethyl)phenyl,    -   (3-amino)phenyl,    -   (3-methylamino)phenyl,    -   (3-dimethylamino)phenyl,    -   (5-amidino-2-hydroxy)phenyl,    -   (1-amidino)piperid-3-yl,    -   (1-amidino)pyrrolid-3-yl,    -   (5-amidino)thien-2-yl,    -   (5-amidino)furan-2-yl,    -   (5-amidino)-1,3-oxazol-2-yl,    -   (2-amidino)-1,3-oxazol-5-yl,    -   1H-pyrazol-5-yl, tetrahydro-1H-pyrazol-3-yl,    -   (1-amidino)tetrahydro-1H-pyrazol-3-yl,    -   (2-amidino)-1H-imidazol-4-yl,    -   (2-amino)-1H-imidazol-4-yl,    -   (5-amidino)-1H-imidazol-2-yl,    -   (5-amino)-1H-imidazol-2-yl,    -   pyridin-3-yl,    -   (4-amino)pyridin-3-yl,    -   (4-dimethylamino)pyridin-3-yl,    -   (6-amino)pyridin-2-yl,    -   (6-amidino)pyridin-2-yl,    -   (2-amino)pyridin-4-yl,    -   (2-amidino)pyridin-4-yl,    -   (2-amidino)pyrimid-4-yl,    -   (2-amino)pyrimidin-4-yl,    -   (4-amidino)pyrimid-2-yl,    -   (4-amino)pyrimidin-2-yl,    -   (6-amidino)pyrazin-2-yl,    -   (6-amino)pyrazin-2-yl,    -   (4-amidino)-1,3,5-triazin-2-yl,    -   (4-amino)-1,3,5-triazin-2-yl,    -   (3-amidino)-1,2,4-triazin-5-yl,    -   (3-amino)-1,2,4-triazin-5-yl,    -   (3-amidino)benzyl,    -   (3-amino)benzyl-₇    -   (3-aminomethyl)benzyl,    -   (1-amidino)piperid-3-ylmethyl,    -   (1-amidino)pyrrolid-3-ylmethyl,    -   (1-amidino)thien-2-ylmethyl,    -   (5-amidino)furan-2-ylmethyl, (5-amidino)oxazol-2-ylmethyl,    -   (2-amidino)imidazol-5-ylmethyl,    -   (5-amidino)imidazol-2-ylmethyl,    -   (6-amidino)pyridin-2-ylmethyl,    -   (6-amino)pyridin-2-ylmethyl,    -   (2-amidino)pyrimidin-4-ylmethyl,    -   (2-amino)pyrimidin-4-ylmethyl,    -   (4-amidino)pyrimidin-2-ylmethyl,    -   (4-amino)pyrimidin-2-ylmethyl,    -   (6-amidino)pyrazin-2-ylmethyl,    -   (6-amino)pyrazin-2-ylmethyl,    -   3-aminocyclohexyl,    -   3-amidinocyclohexyl,    -   3-aminocyclohexylmethyl,    -   3-amidinocyclohexylmethyl,    -   3-aminocyclopentyl,    -   3-amidinocyclopentyl,    -   3-aminocyclopentylmethyl, and    -   3-amidinocyclopentylmethyl; and-   R₈ is selected from H,    -   Cl,    -   F,    -   SH,    -   SMe,    -   CF₃,    -   CH₃,    -   CO₂H,    -   CO₂Me,    -   CN,    -   C(═NH)NH₂,    -   C(═NH)NHOH,    -   C(═NH)NHNH₂,    -   C(═O)NH₂,    -   CH₂OH,    -   CH₂NH₂,    -   NO₂,    -   OH,    -   OMe,    -   OCH₂Ph,    -   OCH₂CO₂H,    -   O(CH₂)₂CO₂H,    -   O(CH₂)₃CO₂H,    -   NHCH₂CO₂H,    -   NH(CH₂)₂CO₂H,    -   NH(CH₂)₃CO₂H,    -   OCH₂CH₂OH,    -   OCH₂(1H-tetrazol-5-yl),    -   NH₂,    -   NHButyl,    -   NMe₂,    -   NHPh,    -   NHCH₂Ph,    -   NHC(═O)Me,    -   NHC(═O)c-Hexyl,    -   NHC(═O)CH₂c-Hexyl,    -   NHC(═O)Ph,    -   NHC(═O)CH₂Ph,    -   NHS(═O)₂Me,    -   NHS(═O)₂c-Hexyl,    -   NHS(═O)₂CH₂c-Hexyl,    -   NHS(═O)₂Ph, and    -   NHS(═O)₂CH₂Ph;        or stereoisomers or pharmaceutically acceptable salts, esters,        amides, or prodrugs thereof.

The most preferred compounds provided by this invention are compounds ofFormula IV

wherein X, Y, R₇, R₉, and—are as follows:

-   X is selected from (CH₂)₅,    -   (CH₂)₄    -   (CH₂)₆,    -   CH₂C(═O)NHCH₂CH₂,    -   CH₂CH₂NHC(═O)CH₂,    -   (CH₂)₂NH(CH₂)₂,    -   (CH₂)₂O(CH₂)₂,    -   C₆H₄,    -   CH₂C₆H₄,    -   C₆H₄CH₂,    -   C₆H₁₀,    -   CH₂C₆H₁₀,    -   C₆H₁₀CH₂,    -   C₅H₈,    -   CH₂C₅H₈,    -   C₅H₈CH₂, and    -   CH₂CH═CHCH₂CH₂;-   Y is selected from 2,6-dimethylpiperidinyl,    -   piperidinyl,    -   2,2,6,6-tetramethyl-piperidinyl-4-one,    -   (2-carboxy)piperidinyl,    -   (3-carboxy)piperidinyl,    -   (4-carboxy)piperidinyl,    -   3,5-dimethylpiperidinyl,    -   (4-hydroxy)piperidinyl,    -   (2-imino)piperidinyl,    -   piperidin-4-one-yl,    -   (2-dimethylaminomethyl)-piperidinyl,    -   (4-dimethylamino)-piperidinyl,    -   (4-sulphonyloxy)-piperidinyl,    -   (2-phenyl)piperidinyl,    -   2,5-dimethylpyrrolidinyl,    -   pyrrolidinyl,    -   (2-carboxy)pyrrolidinyl,    -   (3-N-acetyl-N-methyl)pyrrolidinyl,    -   (3-amino)pyrrolidinyl,    -   (2,5-bis-methoxymethyl)-pyrrolidinyl,    -   2-hydroxymethyl-pyrrolidinyl,    -   2-hydroxymethyl-5-methyl-pyrrolidinyl,    -   diisopropylamino,    -   diethylamino,    -   methylamino,    -   1-methyl-4,5-dihydro-1H-imidazol-2-yl,    -   2,5-dimethyl-1H-1-imidazolyl,    -   morpholinyl,    -   2,6-dimethylmorpholinyl,    -   piperazinyl,    -   2,6-dimethylpiperazinyl,    -   1H-pyrazolyl,    -   tetrahydro-1H-pyrazolyl, and    -   2,5-dimethyltetrahydro-1H-1-pyrazolyl;-   R₇ is selected from (3-amidino)phenyl,    -   (3-hydroxy)phenyl,    -   [3-hydroxylamino(imino)methyl]-phenyl,    -   [3-hydrazino(imino)methyl]-phenyl,    -   (3-aminomethyl)phenyl,    -   (3-amino)phenyl,    -   (3-methylamino)phenyl,    -   (3-dimethylamino)phenyl,    -   (5-amidino-2-hydroxy)phenyl,    -   (1-amidino)piperid-3-yl,    -   (1-amidino)pyrrolid-3-yl,    -   (5-amidino)thien-2-yl,    -   (5-amidino)furan-2-yl,    -   (5-amidino)-1,3-oxazol-2-yl,    -   (2-amidino)-1,3-oxazol-5-yl,    -   1H-pyrazol-5-yl,    -   tetrahydro-1H-pyrazol-3-yl,    -   (1-amidino)tetrahydro-1H-pyrazol-3-yl,    -   (2-amidino)-1H-imidazol-4-yl,    -   (2-amino)-1H-imidazol-4-yl,    -   (5-amidino)-1H-imidazol-2-yl,    -   (5-amino)-1H-imidazol-2-yl,    -   pyridin-3-yl,    -   (4-amino)pyridin-3-yl,    -   (4-dimethylamino)pyridin-3-yl,    -   (6-amino)pyridin-2-yl,    -   (6-amidino)pyridin-2-yl,    -   (2-amino)pyridin-4-yl,    -   (2-amidino)pyridin-4-yl,    -   (2-amidino)pyrimid-4-yl,    -   (2-amino)pyrimidin-4-yl,    -   (4-amidino)pyrimid-2-yl,    -   (4-amino)pyrimidin-2-yl,    -   (6-amidino)pyrazin-2-yl,    -   (6-amino)pyrazin-2-yl,    -   (4-amidino)-1,3,5-triazin-2-yl,    -   (4-amino)-1,3,5-triazin-2-yl,    -   (3-amidino)-1,2,4-triazin-5-yl,    -   (3-amino)-1,2,4-triazin-5-yl,    -   (3-amidino)benzyl,    -   (3-amino)benzyl,    -   (3-aminomethyl)benzyl,    -   (1-amidino)piperid-3-ylmethyl,    -   (1-amidino)pyrrolid-3-ylmethyl,    -   (5-amidino)thien-2-ylmethyl,    -   (5-amidino)furan-2-ylmethyl,    -   (5-amidino)oxazol-2-ylmethyl,    -   (2-amidino)imidazol-5-ylmethyl,    -   (5-amidino)imidazol-2-ylmethyl,    -   (6-amidino)pyridin-2-ylmethyl,    -   (6-amino)pyridin-2-ylmethyl,    -   (2-amidino)pyrimidin-4-ylmethyl,    -   (2-amino)pyrimidin-4-ylmethyl,    -   (4-amidino)pyrimidin-2-ylmethyl,    -   (4-amino)pyrimidin-2-ylmethyl,    -   (6-amidino)pyrazin-2-ylmethyl,    -   (6-amino)pyrazin-2-ylmethyl,    -   3-aminocyclohexyl,    -   3-amidinocyclohexyl,    -   3-aminocyclohexylmethyl,    -   3-amidinocyclohexylmethyl,    -   3-aminocyclopentyl,    -   3-amidinocyclopentyl,    -   3-aminocyclopentylmethyl, and    -   3-amidinocyclopentylmethyl; and-   R₈ is selected from H,    -   Cl,    -   F,    -   SH,    -   SMe,    -   CF₃,    -   CH₃,    -   CO₂H,    -   CO₂Me,    -   CN,    -   C(═NH)NH₂,    -   C(═NH)NHOH,    -   C(═NH)NHNH₂,    -   C(═O)NH₂,    -   CH₂OH,    -   CH₂NH₂,    -   NO₂,    -   OH,    -   OMe,    -   OCH₂Ph,    -   OCH₂CO₂H,    -   O(CH₂)₂CO₂    -   H,    -   O(CH₂)₃CO₂H,    -   NHCH₂CO₂H,    -   NH(CH₂)₂CO₂H,    -   NH(CH₂)₃CO₂H,    -   OCH₂CH₂OH,    -   OCH₂(1H-tetrazol-5-yl),    -   NH₂,    -   NHButyl,    -   NMe₂,    -   NHPh,    -   NHCH₂Ph,    -   NHC(═O)Me,    -   NHC(═O)c-Hexyl,    -   NHC(═O)CH₂c-Hexyl,    -   NHC(═O)Ph,    -   NBC(═O)CH₂Ph,    -   NHS(═O)₂Me,    -   NHS(═O)₂c-Hexyl,    -   NHS(═O)₂CH2c-Hexyl,    -   NHS(═O)₂Ph, and    -   NHS(═O)₂CH₂Ph;        or stereoisomers or pharmaceutically acceptable salts, esters,        amides, or prodrugs thereof.

In one embodiment of Formula IV, Y, R₇, and R₈ are as above, and X is(CH₂)₅.

In another embodiment of Formula IV, X, R₇, and R₈ are as above and Y is2,6-dimethylpiperidinyl.

In another embodiment of Formula IV, X, Y, and R₈ are as above and R₇ is(2-hydroxy-5-amidino)phenyl.

In another embodiment of Formula IV, X, Y, and R₇ are as above and R₈ isH.

In another embodiment of Formula IV, R₇ is as above, and X is (CH₂)₅, Yis 2,6-dimethylpiperidinyl, and R₈ is H.

In another embodiment of Formula IV, R₇ is as above, and X is (CH₂)₅ andY is 2,5-dimethylpyrrolidinyl.

Representative compounds of the present invention include:

-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-hydroxyphenyl)-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidohydrazide;-   3-[3-(Aminomethyl)phenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-(3-Aminophenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-[3-(methylamino)phenyl]-2(1H)-quinolinone;-   3-[3-(Dimethylamino)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)tetrahydro-1(2H)-pyridinecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1-pyrrolidinecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-thiophenecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)₂-furancarboximidamide;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3-oxazole-5-carboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3-oxazole-2-carboximidamide;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(1H-pyrazol-3-yl)-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-tetrahydro-1H-pyrazol-3-yl-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1-pyrazolidinecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1H-imidazole-2-carboximidamide;-   3-(2-Amino-1H-imidazol-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1H-imidazole-5-carboximidamide;-   3-(5-Amino-1H-imidazol-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl)pentyl-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-3-(3-pyridinyl)-2(1H)-quinolinone;-   3-(6-Amino-3-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-[6-(Dimethylamino)-3-pyridinyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-(6-Amino-2-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyridinecarboximidamide;-   3-(2-Amino-4-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyridinecarboximidamide;-   4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyrimidinecarboximidamide;-   3-(2-Amino-4-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-4-pyrimidinecarboximidamide;-   3-(4-Amino-2-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2(1H)quinolinone;-   6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyrazinecarboximidamide;-   3-(6-Amino-2-pyrazinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2(1H)-quinolinone;-   4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3,5-triazine-2-carboximidamide;-   3-(4-Amino-1,3,5-triazin-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,2,4-triazine-3-carboximidamide;-   3-(3-Amino-1,2,4-triazin-5-yl)-1-S-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)quinolinone;-   3-[(−5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]benzenecarboximidamide;-   3-(3-Aminobenzyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-[3-(Aminomethyl)benzyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1-pyrrolidinecarboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-thiophenecarboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-furancarboximidamide;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1,3-oxazole-5-carboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1H-imidazole-2-carboximidamide;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1H-imidazole-5-carboximidamide;-   6-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyridinecarboximidamide;-   3-[(6-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   4-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyrimidinecarboximidamide;-   3-[(2-Amino-4-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-4-pyrimidinecarboximidamide;-   3-[(4-Amino-2-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   6-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyrazinecarboximidamide;-   3-((6-Amino-2-pyrazinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-(3-Aminocyclohexyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)cyclohexanecarboximidamide;-   3-[(3-Aminocyclohexyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]cyclohexanecarboximidamide;-   3-(3-Aminocyclopentyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;-   3-(−5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)cyclopentanecarboximidamide;-   3-[(3-Aminocyclopentyl)methyl]-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2M)-pyridinyl    pentyl-2(1 h)quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methylcyclopentanecarboximidamide;-   3-(1-4[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]butyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   2-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl)-N-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;-   3-f    3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl)-N-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;-   3-1-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl)-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-[1-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-(14-[(2R,6S)-2,6-Dimethyltetrahydro-1(2M)-pyridinyl]phenyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide,-   3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)cyclohexylmethyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]methylcyclopentyl)₂-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-[2-Oxo-1-(5-piperidinopentyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-2-Oxo-1-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-piperidinecarboxylic    acid;-   1-5-[3-3-[Amino(imino)methyl)phenyl-2-oxo-1(2H)-quinolinyl]pentyl-3-piperidinecarboxylic    acid;-   1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-4-piperidinecarboxylic    acid;-   3-1-[5-(3,5-Dimethylpiperidino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(4-Hydroxypiperidino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(2-Iminopiperidino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(4-oxopiperidino)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-[1-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-5-[4-(Dimethylamino)piperidinopentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide,    1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)quinolinyl]pentyl 1    piperidinesulfonic acid;-   3-2-Oxo-1-[5-(2-phenylpiperidino)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(1-pyrrolidinyl)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-pyrrolidonecarboxylic    acid;-   N-(1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyltetrahydro-1H-pyrrol-3-yl)-N-methylacetamide;-   3-1-[5-(3-Amino-1-pyrrolidinyl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-(1-5-[2,5-bis(Methoxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-1-[5-(Diisopropylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(Diethylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(Methylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-[1-(5-Morpholinopentyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-1-[5-(3,5-Dimethylmorpholino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-[2-oxo-1-(5-Piperazinopentyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-1-[5-(2,6-Dimethylpiperazino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(1H-pyrazol-1-yl)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-[2-Oxo-1-(5-tetrahydro-1H-pyrazol-1-yl)pentyl]-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-1-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-(7-Chloro-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)pentyl-7-fluoro-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-sulfanyl-1,2-dihydro-3-quinolinyl)benzenecarboximidamide,    3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(methylsulfanyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-7-methyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxylic    acid;-   Methyl    3-3-[amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl    pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxylate;-   3-(7-Cyano-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-N-hydroxy-2-oxo-1,2-dihydro-7-quinolinecarboximidamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H-pyridinyl)pentyl-7-[hydrazino(imino)methyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H-pyridinyl]pentyl-7-(hydroxymethyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(7-(Aminomethyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2M)-pyridinyl]pentyl-7-nitro-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methoxy-2-oxo-12-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Benzyloxy)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy)acetic    acid;-   3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]propanoic    acid;-   4-[(3-3-[Amino(imino)methyl]phenyl    1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]butanoic    acid;-   2-[(3-3-[Amino(imino)methyl]phenyl-1-5-1(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]acetic    acid;-   3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]propanoic    acid;-   4-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]butanoic    acid;-   3-[1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(2-hydroxyethoxy)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-(1H-1,2,3,4-tetraazol-5-ylmethoxy)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;-   3-(7-Amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Butylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Dimethylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-Anilino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Benzylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)acetamide;-   N-(3-3-(Amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)cyclohexanecarboxamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-cyclohexylacetamide;-   N-(3-3-(Amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)benzenecarboxamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-phenylacetamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-pentyl-7-[(methylsulfonyl)amino]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-(7-[(Cyclohexylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-[(Cyclohexylmethyl)sulfonyl]amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2-oxo-7-[(phenylsulfonyl)amino]3-1,2-dihydro-3-quinolinylbenzenecarboximidamide;-   3-(7-[(Benzylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-hydroxyphenyl)-3,4-dihydro-2(1H)quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidohydrazide;-   3-[3-(Aminomethyl)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1    h)-quinolinone;-   3-(3-Aminophenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-[3-(methylamino)phenyl]-3,4-dihydro-2(1H)-quinolinone;-   3-[3-(Dimethylamino)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide;-   3-(1-5-{(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)tetrahydro-1(2H)-pyridinecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1-pyrrolidinecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-thiophenecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-furancarboximidamide;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,3-oxazole-5-carboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,3-oxazole-2-carboximidamide;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(1H-pyrazol-3-yl)-3,4-dihydro-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-tetrahydro-1H-pyrazol-3-yl-3,4-dihydro-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1-pyrazolidinecarboximidamide;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1H-imidazole-2-carboximidamide;-   3-(2-Amino-1H-imidazol-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1H-imidazole-5-carboximidamide;-   3-(5-Amino-1H-imidazol-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-pyridinyl)-3,4-dihydro-2(1H)-quinolinone;-   3-(6-Amino-3-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-[6-(Dimethylamino)-3-pyridinyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-(6-Amino-2-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyridinecarboximidamide;-   3-(2-Amino-4-pyridinyl)-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   4-(1-5-[(2R,6S)2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyridinecarboximidamide;-   4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyrimidinecarboximidamide;-   3-(2-Amino-4-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-4-pyrimidinecarboximidamide;-   3-(4-Amino-2-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyrazinecarboximidamide;-   3-(6-Amino-2-pyrazinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,3,5-triazine-2-carboximidamide;-   3-(4-Amino-1,3,5-triazin-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,2,4-triazine-3-carboximidamide;-   3-(3-Amino-1,2,4-triazin-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(I    1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]benzenecarboximidamide;-   3-(3-Aminobenzyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-[3-(Aminomethyl)benzyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1-pyrrolidinecarboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-thiophenecarboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo    1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-furancarboximidamide;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1,3-oxazole-5-carboximidamide;-   5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1H-imidazole-2-carboximidamide;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1H-imidazole-5-carboximidamide;-   6-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-pyridinecarboximidamide;-   3-[(6-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1)-quinolinone;-   4-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-pyrimidinecarboximidamide;-   3-[(2-Amino-4-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-4-pyrimidinecarboximidamide;-   3-[(4-Amino-2-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   6-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-pyrazinecarboximidamide;-   3-[(6-Amino-2-pyrazinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-(3-Aminocyclohexyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)cyclohexanecarboximidamide;-   3-[(3-Aminocyclohexyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]cyclohexanecarboximidamide;-   3-(3-Aminocyclopentyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)cyclopentanecarboximidamide;-   3-[(3-Aminocyclopentyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;-   3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]cyclopentanecarboximidamide;-   3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]butyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   2-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;-   3-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;-   3-1-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl)ethoxyethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1,    [(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]benzyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(14-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-cyclopentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-(E)-5-[(2R,6S)2,6-Dimethyltetrahydro-1(2M-pyridinyl-2-pentenyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-[2-Oxo-1(5-piperidinopentyl)    1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-2-Oxo-1-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-piperidinecarboxylic    acid;-   1-S-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-3-piperidinecarboxylic    acid;-   1-5-[3-3-[(Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-4-piperidinecarboxylic    acid;-   3-1-[5-(3,5-Dimethylpiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(4-Hydroxypiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-(5-(2-Iminopiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(4-oxopiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-[1-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-5-[4-(Dimethylamino)piperidino]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   1-5-(3-3-[amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-4-piperidinesulfonic    acid;-   3-2-Oxo-1-[5-(2-phenylpiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(1-pyrrolidinyl)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-pyrrolidinecarboxylic    acid;-   N-(1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl    pentyltetrahydro-1H-pyrrol-3-yl)-N-methylacetamide;-   3-1-[5-(3-Amino-1-pyrrolidinyl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-(1-5-[2,5-bis(Methoxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-1-[5-(Diisopropylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(Diethylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(Methylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-5-(1-Methyl-1H-imidazol-2-yl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-1-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-[1-(5-Morpholinopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-1-[5-(3,5-Dimethylmorpholino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-[2-Oxo-1-(5-piperazino)pentyl]-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-1-[5-(2,6-Dimethylpiperazino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-2-Oxo-1-[5-(1H-pyrazol-1-yl)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-[2-Oxo-1-(5-tetrahydro-1H-pyrazol-1-yl)pentyl)-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-1-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-(7-Chloro-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-fluoro-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-sulfanyl-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(methylsulfanyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxylic    acid;-   methyl    3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxylate;-   3-(7-Cyano-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-N-hydroxy-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboximidamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-[hydrazino(imino)methyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(7-(Aminomethyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-nitro-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methoxy-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Benzyloxy)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]acetic    acid;-   3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]propanoic    acid;-   4-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]butanoic    acid;-   2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]acetic    acid;-   3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]propanoic    acid;-   4-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]butanoic    acid;-   3-[1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(2-hydroxyethoxy)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-(1H-1,2,3,4-tetraazol-5-ylmethoxy)-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;-   3-(7-Amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Butylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Dimethylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-Anilino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-(Benzylamino)    1-5-((2R,6S)2,6-dimethyltetrahydro-[(21)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)acetamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)cyclohexanecarboxamide;-   N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-cyclohexylacetamide;-   N-(3-3-[Amino(imino)methylphenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)benzenecarboxamide;-   3N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-phenylacetamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-[(methylsulfonyl)amino]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-(7-[(Cyclohexylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1    (2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-(7-[(Cyclohexylmethyl)sulfonyl]amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;-   3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-[(phenylsulfonyl)amino]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;-   3-(1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-oxo-1,2-dihydro-quinolin-3-yl}-4-hydroxy-benzamidine;-   4-{1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl}-benzoic    acid methyl ester;-   4-{1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl}-benzamidine;-   3-Phenyl-1-(5-piperidin-1-yl-pentyl)-1H-quinolin-2-one;-   3-{1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl}-benzamide;-   3-Phenyl-1-(5-piperidin-1-yl-pentyl)-3,4-dihydro-1H-quinolin-2-one;-   2(1H)-Quinolinone, 1,1′-(1,5-pentylidene)bis[3,4-dihydro-3-phenyl-,    (±)-;-   3-(7-[(Benzylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;    and-   1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-(4-methoxyphenyl)-3,4-dihydro-1H-quinolin-2-one.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl” means a straight, branched, saturated or unsaturatedcarbon chain having from 1 to 20 carbon atoms. Typical alkyl groupsinclude methyl, isobutyl, pentyl, 2-methyl-pentyl, pent-1,4-dienyl,but-1-enyl and the like.

The term “cycloalkyl” means a saturated or unsaturated carbon chainwhich forms a ring having from 3 to 20 carbon atoms. Typical examplesinclude cyclopropyl, cyclohexyl and the like.

The term “cycloalkylalkyl” means a cycloalkyl group attached to an alkylgroup wherein “cycloalkyl” and “alkyl” are as defined above andincludes, for example, cyclopropylmethyl, cyclopentylethyl and the like.

The term “heteroalkyl” means a straight, branched, saturated orunsaturated carbon chain having from 1 to 20 carbon atoms wherein one ormore carbon atoms is replaced by a heteroatom selected from oxygen,nitrogen, sulfur, sulphoxide, or sulphone. Typical “heteroalkyl” groupsinclude methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyland the like.

The term “aryl” represents an unsaturated carbocyclic ring(s) of 6 to 16carbon atoms which is optionally substituted with OH, O(alkyl), SH,S(alkyl), amine, halogen, acid, ester, amide, alkyl ketone, aldehyde,nitrile, fluoroalkyl, nitro, sulphone, sulfoxide, or (C₁₋₆)alkyl.Typical rings include phenyl, naphthyl, phenanthryl, and anthracenyl.Preferred aryl rings are phenyl, substituted phenyl, and naphthyl.

The term “arylalkyl” means an aromatic radical attached to an alkylradical wherein “aryl” and “alkyl” are as defined above and includes,for example, benzyl and naphthylmethyl.

The term “heterocycle” means a saturated or unsaturated mono- orpolycyclic (i.e., bicyclic) ring incorporating one or more (i.e., 1-4)heteroatoms selected from N, O, and S. It is understood that aheterocycle is optionally substituted with OH, O(alkyl), SH, S(alkyl),amine, halogen, acid, ester, amide, alkyl ketone, aldehyde, nitrile,fluoroalkyl, nitro, sulphone, sulfoxide, or C₁₋₆ alkyl. Examples ofsuitable monocyclic heterocycles include, but are not limited tosubstituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl,pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl,thietanyl, oyetanyl. Preferred monoydicheterocycles include, but are notlimited to, 2- or 3-thienyl; 2- or 3-furanyl; 1-, 2-, or 3-pyrrolyl; 1-,2-, 4-, or 5-imidazolyl; 1-, 3-, 4-, or 5-pyrazolyl; 2-, 4-, or5-thiazolyl; 3-, 4- or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl; 3-, 4-, or5-isoxazolyl; 1-, 3-, or 5-triazolyl; 1-, 2-, or 3-tetrazolyl; 2-, 3-,4-pyridinyl; 2-pyrazinyl; 2-, 4-, or 5-pyrimidinyl; 1-, 2-, 3-, or4-piperidinyl; 1-, 2-, or 3-pyrrolidinyl; 1-, or 2-piperazinyl; 1-, 2-,or 3-azetidinyl; 1- or 2-aziridinyl; 2-, 3-, or 4-morpholinyl; 2- or3-thietanyl; 2- or 3-oxetanyl. Examples of suitable bicyclicheterocycles include, but are not limited to, indolizinyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl,and preferably 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 1-, 2-, 3-, 5-, 6-,7-, or 8-indolizinyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl; 2-, 3-,4-, 5-, 6-, or 7-benzothienyl; 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 1-,2-, 4-, 5-, 6-, or 7-benzimidazolyl; 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.

The term “heteroatom” as used herein represents oxygen, nitrogen, orsulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO₂) unlessotherwise indicated. It is understood that alkyl chains interrupted byone or more heteroatoms means that a carbon atom of the chain isreplaced with a heteroatom having the appropriate valency. Preferably,an alkyl chain is interrupted by 1 to 4 heteroatoms and that twoadjacent carbon atoms are not both replaced. Examples of such groupsinclude methoxymethyl, 3-thiomethylpropyl, and2-thiomethoxyethoxymethyl.

The term “amine” refers to a group such as NH₂, NHalkyl, NH(cycloalkyl),NH(cycloalkylalkyl), NH(aryl), NH(arylalkyl), NH(heteroaryl),NH(heteroarylalkyl), N(alkyl)(alkyl), N(alkyl)(cycloalkyl),N(alkyl)(cycloalkylalkyl), N(alkyl)(aryl), N(alkyl)(arylalkyl),N(alkyl)(heteroaryl), N(alkyl)(heteroarylalkyl),N(cycloalkyl)(cycloalkyl), N(cycloalkyl)(cycloalkylalkyl),N(cycloalkyl)(aryl), N(cycloalkyl)(arylalkyl),N(cycloalkyl)(heteroaryl), N(cycloalkyl)(heteroarylalkyl),N(cycloalkylalkyl)(cycloalkylalkyl), N(cycloalkylalkyl)(aryl),N(cycloalkylalkyl)(arylalkyl), N(cycloalkylalkyl)(heteroaryl),N(cycloalkylalkyl)(heteroarylalkyl), N(aryl)(cycloalkylalkyl),N(aryl)(aryl), N(aryl)(arylalkyl), N(aryl)(heteroaryl),N(aryl)(heteroarylalkyl), N(arylalkyl)(arylalkyl),N(arylalkyl)(heteroaryl), N(arylalkyl)(heteroarylalkyl),N(heteroaryl)(heteroaryl), N(heteroaryl)(heteroarylalkyl),N(heteroarylalkyl)(heteroarylalkyl).

The term “acid” refers to C(═O)OH.

The term “ketone” refers to C(═O)alkyl, C(═O)cycloalkyl,C(═O)cycloalkylalkyl, C(═O)aryl, C(═O)arylalkyl, C(═O)heteroaryl,C(═O)heteroarylalkyl.

The term “ester” refers to a group such as C(═O)Oalkyl,C(═O)Ocycloalkyl, C(═O)Ocycloalkylalkyl, C(═O)Oaryl, C(═O)Oarylalkyl,C(═O)Oheteroaryl, C(═O)Oheteroarylalkyl.

The term “amide” refers to a group such as, C(═O)NH₂, C(═O)NHalkyl,C(═O)NH(cycloalkyl), C(═O)NH(cycloalkylalkyl), C(═O)NH(aryl),C(═O)NH(arylalkyl), C(═O)NH(heteroaryl), C(═O)NH(heteroarylalkyl),C(═O)N(alkyl)(alkyl), C(═O)N(alkyl)(cycloalkyl),C(═O)N(alkyl)(cycloalkylalkyl), C(O)N(alkyl)(aryl),C(═O)N(alkyl)(arylalkyl), C(═O)N(alkyl)(heteroaryl),C(═O)N(alkyl)(heteroarylalkyl), C(═O)N(cycloalkyl)(cycloalkyl),C(═O)N(cycloalkyl)(cycloalkylalkyl), C(═O)N(cycloalkyl)(aryl),C(═O)N(cycloalkyl)(arylalkyl), C(═O)N(cycloalkyl)(heteroaryl),C(═O)N(cycloalkyl)(heteroarylalkyl),C(═O)N(cycloalkylalkyl)(cycloalkylalkyl), C(═O)N(cycloalkylalkyl)(aryl),C(═O)N(cycloalkylalkyl)(arylalkyl), C(═O)N(cycloalkylalkyl)(heteroaryl),C(═O)N(cycloalkylalkyl)(heteroarylalkyl), C(═O)N(aryl)(cycloalkylalkyl),C(═O)N(aryl)(aryl), C(═O)N(aryl)(arylalkyl), C(═O)N(aryl)(heteroaryl),C(═O)N(aryl)(heteroarylalkyl), C(═O)N(arylalkyl)(arylalkyl),C(═O)N(arylalkyl)(heteroaryl), C(═O)N(arylalkyl)(heteroarylalkyl),C(═O)N(heteroaryl)(heteroaryl), C(═O)N(heteroaryl)(heteroarylalkyl),C(═O)N(heteroarylalkyl)(heteroarylalkyl).

The term “urea” refers to a group such as NHC(═O)N(alkyl)(alkyl),NHC(═O)N(alkyl)(cycloalkyl), NHC(═O)N(alkyl)(cycloalkylalkyl),NHC(═O)N(alkyl)(aryl), NHC(═O)N(alkyl)(arylalkyl),NHC(═O)N(alkyl)(heteroaryl), NHC(═O)N(alkyl)(heteroarylalkyl),NHC(═O)N(cycloalkyl)(cycloalkyl), NHC(═O)N(cycloalkyl)(cycloalkylalkyl),NHC(═O)N(cycloalkyl)(aryl), NHC(═O)N(cycloalkyl)(arylalkyl),NHC(═O)N(cycloalkyl)(heteroaryl), NHC(═O)N(cycloalkyl)(heteroarylalkyl),NHC(═O)N(cycloalkylalkyl)(cycloalkylalkyl),NHC(═O)N(cycloalkylalkyl)(aryl), NHC(═O)N(cycloalkylalkyl)(arylalkyl),NHC(═O)N(cycloalkylalkyl)(heteroaryl),NHC(═O)N(cycloalkylalkyl)(heteroarylalkyl),NHC(═O)N(aryl)(cycloalkylalkyl), NHC(═O)N(aryl)(aryl),NHC(═O)N(aryl)(arylalkyl), NHC(═O)N(aryl)(heteroaryl),NHC(═O)N(aryl)(heteroarylalkyl), NHC(═O)N(arylalkyl)(arylalkyl),NHC(═O)N(arylalkyl)(heteroaryl), NHC(═O)N(arylalkyl)(heteroarylalkyl),NHC(═O)N(heteroaryl)(heteroaryl), NHC(═O)N(heteroaryl)(heteroarylalkyl),NHC(═O)N(heteroarylalkyl)(heteroarylalkyl).

The term “halogen” refers to chlorine, fluorine, bromine, and iodine.

The wedge or hash is only one representation of a stereochemicaldescriptor. All stereoisomers, including enantiomers and diastereomers,are included within Formulas I to IV and are provided by this invention.When specific isomers are drawn, they are the preferred isomers.

In some situations, compounds may exist as tautomers. All tautomers areincluded within Formulas I to IV and are provided by this invention.

When compounds are administered, some metabolism may occur. Allmetabolites are included within Formulas I to IV and are provided bythis invention.

When a bond to a substituent is shown to cross the bond connecting 2atoms in a ring, then such substituent may be bonded to any atom in thering, provided the atom will accept the substituent without violatingits valency. When there appears to be several atoms of the substituentthat may bond to the ring atom, then it is the first atom of the listedsubstituent that is attached to the ring.

When a bond is represented by a line such as “---” this is meant torepresent that the bond may be absent or present provided that theresultant compound is stable and of satisfactory valency.

Compounds of the present invention are capable of forming acid additionsalts (see for example, Berge S. M et al., “Pharmaceutical Salts,”Journal of Pharmaceutical Science, 1977: 1-10) with inorganic acids suchas, for example, hydrochloric acid, sulfuric acid and the like as wellas salts derived from organic acids such as, for example, aliphaticmono- and dicarboxylic acids or aliphatic and aromatic sulphonic acids.The acid addition salts are prepared by contacting the free base formwith a sufficient amount of the desired acid to produce the salt. Thefree base form may be regenerated by contacting the salt form with abase. While the free base more may differ from the salt form in terms ofphysical properties, such as solubility, the salts are equivalent totheir respective free bases for the purposes of the present invention.

Certain compounds of the present invention can exist in unsolvated formas well as solvated form including hydrated form. In general, thesolvated form including hydrated form are equivalent to unsolvated formand are intended to be encompassed within the scope of the presentinvention.

“Prodrugs” are intended to include any covalently bonded carrier whichreleases the active parent drug according to Formulas I to IV in vivo.Examples of prodrugs include acetates, formates, benzoate derivatives ofalcohols, and amines present in compounds of Formulas I to IV. They alsoinclude derivatives of the amidine or guanine functionality and wouldinclude C(═NR₃)NH₂ where R₃ is selected from OH, NH₂, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₁₀ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl. Preferredderivatives include examples wherein R₃ is OH, NH₂, methoxy, andethoxycarbonyl.

The following table provides a list of abbreviations and definitionsthereof used in the present invention.

Abbreviation Description AMC Aminomethylcoumarin aPTT Activated partialthromboplastin time BOC Tertiary-butyloxycarbonyl BOP-reagentBenzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphateBz Benzoate CDCl3 Deuterochloroform DMF Dimethyl formamide DMSODimethylsulfoxide ¹H-NMR Proton nuclear magnetic resonance HCl Hydrogenchloride HF Hydrogen fluoride HMPA Hexamethylphosphoramide HPLC highpressure liquid chromatography MOT Mean occlusion time MS (APCI) Massspectrometry (atmospheric pressure CI) MS (CI) Mass spectrometry(chemical ionization) MS (ES) Mass spectrometry (electro spray) NaOHSodium hydroxide nBuLi n-butyl lithium NH4Cl Ammonium chloride Pd/CPalladium on carbon PtO2 Platinum oxide r.t. or RT Room temperature TFATrifluoroacetic acid THF Tetrahydrofuran TT Thrombin time VAZO-522,2′-Azobis-2-methylvaleronitrile

Also provided by this invention is a method for preventing and treatingacute, subacute, and chronic thrombotic disorder in a mammal comprisingadministering to such mammal an effective amount of a compound ofFormulas I to IV. The compounds are useful as anticoagulants for thetreatment and prophylaxis of disorders such as venous and arterialthrombosis, pulmonary embolism, and ischemic events such as myocardialinfarction or cerebral infarction. These compounds also have therapeuticutility for the prevention and treatment of complications of indwellingvascular access ports and arteriovenous shunts and coagulopathiesassociated with cardiopulmonary bypass or other extracorporeal systems.These compounds are useful for preventing or treating unstable angina,refractory angina, intermittent claudication, disseminated intravascularcoagulation, and ocular buildup of fibrin. Since thrombin and serineproteases have also been demonstrated to activate a number of differentcell types, these compounds are useful for the treatment or prophylaxisof septic shock and other inflammatory responses such as acute orchronic atherosclerosis. The compounds also have utility in treatingneoplasia/metastasis and neurodegenerative diseases such as Alzheimer'sand Parkinson's disease. In a preferred method, the thrombotic disorderis selected from venous thrombosis, arterial thrombosis, pulmonaryembolism, myocardial infarction, cerebral infarction, angina, cancer,and diabetes. A further embodiment of this invention is a pharmaceuticalformulation comprising a compound of Formulas I to IV administered witha diluent, excipient, or carrier thereof.

Preparation of Compounds of the Invention

The compounds of Formulas I to IV can be prepared by any of variousmethods known to those skilled in the art of organic chemistry. Thefollowing general schemes represent preferred routes to provide thecompounds of this disclosure. The reactions are typically performed insolvents appropriate to the reagents and substrates employed. It isunderstood that functionality present in the molecule must be compatiblewith the reagents and reaction conditions proposed. Not all compounds ofFormulas I to IV falling into a given class may be compatible with someof the reaction conditions described. Such restrictions are readilyapparent to those skilled in the art of organic synthesis, andalternative methods must then be used.

Quinolinones of Formula I are prepared according to Scheme 1.

Step a:

Treatment of a suitably substituted ortho-nitro benzaldehyde with aphenyl acetic acid, such as 3-cyano-phenylacetic acid, in aceticanhydride and in the presence of base, such as triethylamine, atelevated temperatures, such as at reflux, affords the(E)-2-(3-cyanophenyl)-3-(2-nitrophenyl)prop-2-enoic acid.

Step b:

Reduction of the nitro and alkene functionality is affected by thehydrogenation of the material in the presence of palladium on carbonunder a hydrogen atmosphere. Allowing this reaction to proceed for anextended period, such as 24 hours, results in the formation of the3-(3-cyanophenyl)-1,2,3,4-tetrahydro-2-quinolinone. It is, of course,realized that the cyano substituent may undergo reduction with palladiumon carbon and hydrogen. In some situations, it is necessary to employ analternative substituent that is subsequently converted to the cyanogroup. Such substituents may include an ester, acid, amide, orhydroxymethyl group. Alternatively in situations where concomitantreduction of the substituents on the 3-phenyl ring, such as a bromine orcyano substituent occurs, then reduction to afford the quinolinone isaffected by milder procedures such as the use of Raney nickel as ahydrogenation catalyst. It is also apparent that the NO₂ group may bereduced selectively, with for example, Sn/HCl, H₂S/NH₃ or by carefulhydrogenation. These anilines may then be cyclized with sulfuric acid inacetic anhydride at elevated temperature to afford thedihydroquinolinones according to the procedure of Hino et at., Chem.Pharm. Bull., 1987:2819 and Hey et al., J. Chem. Soc., 1949:3164.

Step c:

Alkylation is typically achieved by treatment with an appropriateelectrophile and by the addition of a base in a dipolar aprotic solvent.Typical conditions include, for example, use of a bis-electrophilicsubstrate such as 1,5-dibromopentane in a dipolar aprotic solvent suchas DMF or DMSO and addition of a base, such as sodium hydride.Alternatively, alkylation can be achieved by the addition of a phasetransfer reagent such as an alkylammonium salt, such asbenzyltriethylammonium chloride, and employing a base such as sodiumethoxide. Reaction rates are typically improved by the application ofheat, and hence, reactions are run at from 0° C. to 70° C.

Step d:

Treatment with an amine, such as cis-2,6-dimethylpiperidine at anelevated temperature such as 50° C. affords the expected N-alkylatedpiperidine. The amine may be used as solvent, or alternatively, theamine may be added in stoichiometric proportions and the reactionmixture refluxed in a solvent such as ethanol, acetonitrile, or toluene.The product, as the appropriate acid addition salt, is then neutralizedby the addition of base such as aqueous potassium hydroxide. Insituations where the amine is volatile, then the reaction mixture isheated, typically from 50° C. to 150° C., in a sealed tube.

Step e:

Conversion of the nitrile to the hydroxyamidine is achieved by allowingthe nitrile to react with hydroxylamine in methanol at room temperature.Typically hydroxylamine hydrochloride is added to the nitrile containingsubstrate at room temperature, and the reaction is initiated by theaddition of base such as potassium carbonate or diisopropylethylamine.The reaction is usually monitored by HPLC to determine the absence ofstarting material, the nitrile, and are typically complete within a24-hour period.

Step f:

The amidoxime is activated by the addition of acetic anhydride oftrifluoroacetic anhydride intermediate in a solvent such as acetic acidor trifluoroacetic acid to afford the O-acylated, which may be isolatedor alternatively used directly in the subsequent reduction step. Thisstep and the subsequent reduction may be combined, i.e., the reductionwith Pd/C is performed in acetic anhydride/acetic acid, ortrifluoroacetic anhydride/trifluoroacetic acid.

Alternatively, treatment of the nitrile with hydrogen chloride in analcoholic solvent affords the corresponding iminoether hydrochloride.These intermediates are then treated with a source of ammonia, forexample, ammonia in methanol, or ammonium chloride, or ammonium acetate,and the mixture is stirred and warmed, if necessary, to afford theamidine.

A procedure for preparing the compounds of Formula I, when the optionalbond is present, is outlined in Scheme 2.

Step a:

Treatment of the 3,4-dihydro-quinolin-2-one with a strong base, such asBuLi and tetramethylpiperidine, affords after exchange with mercury (an)chloride and then addition of the 3-bromo derivative (see Fernandez etal., Synthesis, 1995:1362). Alternatively, the required3-bromohydroquinolin-2-one is available from 3-bromoquinoline via itsN-oxide according to the procedure of Leclerc et al., J. Med. Chem.,1986:2427.

Step b:

A palladium cross-coupling reaction employing an aryl boronic acid, suchas 3-(methoxycarbonyl)phenylboronic acid or aryl stannane, effects thetransformation of the vinylic bromide to the corresponding aryl alkene.Typically, palladium (0) tetrakis triphenylphosphine is added to amixture of the halide and aryl boronic acid in a solvent such as amixture of toluene and DMF, and mixture is then warmed to about 100° C.under a nitrogen atmosphere. The procedure is analogous to thatdescribed by Timari et al., Syn. Lett., 1997:1067. An alternativeprocedure employing aryl zinc halide organometalics has also beendescribed by Leclerc et al., J. Med. Chem., 1986:2427.

Alternatively, according to the procedure of Meng et al., J. Het. Chem.,1991:1481, the vinyl halide may be irradiated with a mercury lamp in aquartz vessel in the presence of, for example, thiophene to afford the3-(2-thienyl). Use of benzene as a solvent would afford the 3-phenyladduct.

Step c:

Alkylation is typically achieved by treatment with an appropriateelectrophile and by the addition of a base in a dipolar aprotic solvent.Typical conditions include, for example, use of a bis-electrophilicsubstrate such as 1,5-dibromopentane in a dipolar aprotic solvent suchas DMF or DMSO and addition of a base, such as sodium hydride.Alternatively, alkylation can be achieved by the addition of a phasetransfer reagent such as an alkylammonium salt, such asbenzyltriethylammonium chloride, and employing a base such as sodiumethoxide. Reaction rates are typically improved by the application ofheat and hence reactions are un at from 0° C. to 70° C.

Step d:

Treatment with an amine, such as cis-2,6-dimethylpiperidine at anelevated temperature such as 50° C., affords the expected N-alkylatedpiperidine. The amine may be used as solvent, or alternatively, theamine may be added in stoichiometric proportions and the reactionmixture refluxed in a solvent such as ethanol, acetonitrile, or toluene.In situations where the amine is volatile, then the reaction mixture isheated, typically from 50° C. to 150° C., in a sealed tube.

Step e:

Conversion of the methyl ester to the amide is achieved by addition ofammonium hydroxide to a solution of the ester in a solvent such as THF.The reaction mixture is stirred at room temperature for several hours,or alternatively, heated in a sealed tube. An alternative procedure forthe transformation involves conversion of the ester to the correspondingcarboxylic acid with aqueous sodium hydroxide and then conversion of theacid to the corresponding acid chloride with for example oxalylchloride, catalytic DMF, in a solvent such as methylene chloride.Finally, the acid chloride is then treated with aqueous ammonia, whichreadily affords the amide.

Step f:

Addition of trichloroacetyl chloride and triethylamine to a solution ofthe amide in methylene chloride at 0° C. and then stirring with warmingto room temperature over 1 hour readily affords the nitrile.

Steps g and h:

Conversion of the nitrile to the corresponding amidine is achievedaccording to the procedure in Scheme 1.

An alternative procedure to afford the required quinolinones proceedsaccording to the procedure of Chupp et al., J. Het. Chem., 1979:65-71,and outlined in Scheme 3.

Step a:

The aniline is converted to the anilide by treatment with theappropriate arylacetyl chloride in a solvent such as methylene chloride.

Step b:

Treatment of the anilide with Vilsmier reagent, prepared from DMF andphosphoryl chloride in methylene chloride, affords after refluxing theappropriate quinolinone.

Step c:

Treatment with an amine, such as cis-2,6-dimethylpiperidine at anelevated temperature such as 50° C. affords the expected N-alkylatedpiperidine. The amine may be used as sol vent, or alternatively, theamine may be added in stoichiometric proportions and the reactionmixture refluxed in a solvent such as ethanol, acetonitrile or toluene.In situations where the amine is volatile, then the reaction mixture isheated, typically from 50° C. to 150° C., in a scaled tube.

Step d:

The aryl bromide is converted to the corresponding nitrile by, forexample, treatment with copper cyanide in a solvent such as DMF.Typically, the reaction mixture is warmed to 160° C. and maintained atthis temperature for several hours, typically 12, to afford the requiredproduct. Alternatively, the bromide, or iodide, or triflate is convertedto the nitrile by treatment with a transition metal, such as palladiumtetrakis triphenylphosphine and zinc cyanide. The mixture is then warmedin a solvent such as DMF, typically to a temperature of 80° C. forseveral hours or until the reaction is judged complete by, for example,TLC.

Step e:

The nitrile can be converted to the amidine by a numb er of procedures.Two useful procedures include: conversion of the nitrile to thehydroxyamidine which is achieved by allowing the nitrile to react withhydroxylamine in methanol at room temperature. Typically, hydroxylaminehydrochloride is added to the nitrile containing substrate at roomtemperature, and the reaction is initiated by the addition of base suchas potassium carbonate or diisopropylethylamine. The amidoxime may bereduced directly to the amidine, but is typically activated by theaddition of acetic anhydride of trifluoroacetic anhydride to afford theO-acylated, or O-trifluoroacetyl, intermediate, which may be isolated oralternatively used directly in the subsequent reduction step. Thereduction with Pd/C is performed in acetic anhydride/acetic acid, ortrifluoroacetic anhydride/trifluoroacetic acid.

Alternatively, the nitrile may be treated with anhydrous HCl in analcoholic solvent such as methanol to afford the imino etherhydrochloride. This intermediate is then treated with a source ofammonia to afford the expected amidine. Typical sources of ammoniainclude ammonia in methanol or ammonium acetate and ammonium chloride.

Scheme 4 represents an alternative procedure for preparing the requisitecompounds of Formula I. It is particularly useful for introducingheterocyclic functionality at C-3.

Step a:

Treatment of hydroquinolin-2-one with strong base, such as butyllithium, and then tributylstannyl chloride, or hexabutyldistannane,readily affords the corresponding 3-stannyl quinolin-2-one.

Step b:

Addition of the stannane to a solution of 3-bromobenzonitrile in asolvent such as THF, DMF, toluene, or dioxane and in the presence ofpalladium, such as Pd(PPh₃)₂Cl₂, or Pd(PPh₃)₄ with the application ofheat such as reflux, affords the 3-aryl (or 3-heteroaryl adduct in thecase of a halo substituted heterocycle).

Steps c-f:

Typical procedures for these transformations are available in the aboveschemes.

The substituted acetic acid derivatives used in these reactions areprepared by a number of standard procedures. For example, substitutedbenzoic acids or benzoylchlorides may be elaborated according to Scheme5.

Step a:

The substituted benzoic acid is converted to the corresponding acidchloride with, for example, oxalyl chloride and catalytic DMF in asolvent such as methylene chloride at 0° C. to room temperature over aperiod of several hours, such as 1 to 4 hours.

Step b:

Addition of ethereal diazomethane to the acid chloride in, for example,ether at about 5° C. The mixture is then stirred for 1 hour at roomtemperature in which, in advantageous situations, the acid chloridetypically goes into solution and the intermediate diazo speciesprecipitates from solution. Rearrangement with silver oxide, freshlyprepared from silver nitrate and aqueous sodium hydroxide in analcoholic solvent such as methanol at reflux, affords the acetic acidmethyl ester. During the reaction, loss of nitrogen is observed aseffervescence and a silver mirror forms. Replacement of methanol withwater affords the corresponding acid.

Step c:

Conversion of the methyl ester is performed by the addition of aqueousbase, such as lithium hydroxide, in a solvent such as THF/methanol/waterand stirring thc reaction mixture at room temperature for several hours.

Compounds of the present invention are further characterized by theirability to inhibit the catalytic activity of factor Xa, which isdemonstrated in the assay as follows. Compounds of the present inventionmay be prepared for assay by dissolving them in buffer to give solutionsranging in concentrations from 1 to 100 μM. In an assay to determine theinhibitory dissociation constant, Ki, for a given compound, achromogenic or fluorogenic substrate of factor Xa would be added to asolution containing a test compound and factor Xa; the resultingcatalytic activity of the enzyme is spectrophotometrically determined.This assay is well-known to those skilled in the art and is commonlyused to determine antithrombotic activity.

The compounds of the present invention may be used as anti-coagulants invitro or ex vivo as in the case of contact activation with foreignthrombogenic surfaces such as is found in tubing used in extracorporealshunts. The compounds of the invention may also be used to coat thesurface of such thrombogenic conduits. To this end, the compounds of theinvention can be prepared as lyophilized powders, redissolved inisotonic saline or similar diluent, and added in an amount sufficient tomaintain blood in an anticoagulated state.

The therapeutic agents of the present invention may be administeredalone or in combination with pharmaceutically acceptable carriers. Theproportion of each carrier is determined by the solubility and chemicalnature of the compound, the route of administration, and standardpharmaceutical practice. For example, the compounds may be injectedparenterally; this being intramuscularly, intravenously, orsubcutaneously. For parenteral administration, the compound may be usedin the form of sterile solutions containing other solutes, for example,sufficient saline or glucose to make the solution isotonic. Thecompounds may be administered orally in the form of tablets, capsules,or granules containing suitable excipients such as starch, lactose,white sugar and the like. The compounds may also be administeredsublingually in the form of troches or lozenges in which each activeingredient is mixed with sugar or corn syrups, flavoring agents anddyes, and then dehydrated sufficiently to make the mixture suitable forpressing into solid form. The compounds may be administered orally inthe form of solutions which may contain coloring and/or flavoringagents. Typical formulations will contain from about 5 to 95 percent byweight of an invention compound.

The amount of invention compound to be utilized to prevent and treatthrombotic disorders is that amount which is effective to prevent ortreat the condition without causing unacceptable side effects. Sucheffective amounts will be from about 0.01 mg/kg to about 500 mg/kg,preferably from about 1 mg/kg to about 100 mg/kg. Physicians willdetermine the precise dosage of the present therapeutic agents whichwill be most suitable. Dosages may vary with the mode of administrationand the particular compound chosen. In addition, the dosage may varywith the particular patient under treatment.

When the composition is administered orally, a larger quantity of theactive agent will typically be required to produce the same effect ascaused with a smaller quantity given parenterally.

To further assist in understanding the present invention, the followingnon-limiting examples of such factor Xa inhibitory compounds areprovided. The following examples, of course, should not be construed asspecifically limiting the present invention, variations presently knownor later developed, which would be within the purview of one skilled inthe art and considered to fall within the scope of the present inventionas described herein. The preferred compounds as of the present inventionare synthesized using conventional preparative steps and recoverymethods known to those skilled in the art of organic and bio-organicsynthesis, while providing a new and unique combination for the overallsynthesis of each compound. Preferred synthetic routes for intermediatesinvolved in the synthesis, as well as the resulting anti-thromboticcompounds of the present invention, follow.

EXAMPLES

In general, evaporation of reaction mixtures were carried out by rotaryevaporation in vacuo at room temperature 18° C. to 25° C. or at elevatedtemperatures up to 50° C. Chromatography, preferably by medium pressureliquid chromatography, were generally performed on Merck Kieselgel.Reverse phase purification via high pressure liquid chromatography(HPLC), for particular polar compounds, was performed on C-18 reversephase silica gel employing a gradient elution of water and acetonitrilecontaining 0.1% trifluoroacetic acid. The final products displayednuclear magnetic resonance (NMR) spectra and mass spectra consistentwith their assigned structure. Intermediates were not typically fullycharacterized, and their purity was routinely assessed by HPLC or thinlayer chromatography.

Example 1

1-[5(2,6-Dimethylpiperidino)pentyl]-3-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-quinolinone

Step (a) Preparation of:(E)-2-(4-Methoxyphenyl)-3-(2-nitrophenyl)-2-propanoic acid

Into a mixture of o-nitrobenzaldehyde (6.19 g, 41.0 mmol) and4-methoxyphenylacetic acid (1) (10.02 g, 60.3 mmol) in acetic anhydride(20 mL) was added triethylamine (5.66 mL, 41.0 mmol), and the reactionmixture was stirred and heated at reflux (150° C.) for 15 minutes. Thesolution was cooled, diluted with water, and extracted with ethylacetate (3×200 mL). The combined organic extracts were washed with brine(2×100 mL), dried with magnesium sulfate, filtered, evaporated in vacuo,and dried under high vacuum to give 16.20 g as an orange solid. Theproduct (2) was crystallized from ethyl acetate in hexane to give 10.21g (87%) as a solid.

¹H NMR (DMSO, 300 M): δ 8.06 (1H, m), 7.91 (1H, s), 7.47 (3H, m), 6.97(2H, d, J=8.78 Hz), 6.76 (2H, d, J=8.97 Hz), 3.68 (3H, s).Step (b) Preparation of:3-(4-Methoxyphenyl)-1,2,3,4-tetrahydro-2-quinolinone

To (2) (8.22 g, 28.6 mmol) in methanol (100 mL) was added 20% palladiumon carbon (1.0 g) and hydrogenated at 23° C. for 3 hours. The mixturewas filtered through celite and the filter pad washed with THF and DMF.The combined filtrate and washings were concentrated in vacuo. Theproduct (3) was crystallized from methanol in water to give 6.4 g (88%)as a solid.

¹H NMR (DMSO, 300 M): δ 10.26 (1H, s), 7.14 (4H, m), 6.84 (4H, m), 3.69(3H, s), 3.32 (1H, s), 3.11 (2H, d, J=7.69 Hz).Step (c) Preparation of:1-(5-Bromopentyl)-3-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-quinolinone

To the quinolinone (3) (2.02 g, 7.98 mmol) in DMF (10 mL) was addedsodium hydride (0.35 g, 8.75 mmol), and the solution was stirred at 70°C. for fit 15 minutes until bubbling stopped. To this solution was added1,5-dibromopentane (4.37 mL, 31.9 mmol), and the solution was stirred at70° C. for additional 12 hours. The solution was cooled, diluted withwater, and extracted with ethyl acetate (4×200 mL). The combined organicextracts were washed with brine (2×100 mL), dried with magnesiumsulfate, filtered, and evaporated in vacuo. The residue was purified ona silica gel column eluted with 20% to 40% ethyl acetate in hexane. Theproduct (4) was isolated 2.43 g (76%) as a yellow oil.

¹H NMR (DMSO, 300 M): δ 7.26-6.94 (6H, in), 6.80 (2H, d, J=7.69 Hz),3.91-3.78 (2H, m), 3.67 (3H, s), 3.50 (2H, m), 3.33 (1H, s), 3.12 (2H,d, J=6.78 Hz), 1.81 (2H, m), 1.57 (2H, m), 1.41 (2H, m).Step (d) Preparation of:1-[5-(2,6-Dimethylpiperidino)pentyl]-3-(4-methoxyphenyl)-1,2,3,4-tetrahydro-2-quinolinone

To (4) (0.32 g, 0.795 mmol) was added cis-2,6-dimethylpiperidine (6.2mL, 46.0 mmol), and the solution was stirred at 70° C. for 48 hours. Thesolution was cooled, diluted with water, and extracted with ethylacetate (3×100 mL). The combined organic extracts were washed withsaturated sodium bicarbonate (2×100 mL), washed with brine (2×100 mL),dried with magnesium sulfate, filtered, and evaporated in vacuo. Theresidue was purified by preparative HPLC (Vydac 218TP 1022 C18, elutedwith a mixture of solvents consisting of (i) 0.1% trifluoroacetic acidin water, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 95:5 (i):(ii) to 60:40 (i):(ii) over 90 minutes, flow rate 20mL/minute, λ=214 nM) and was lyophilized to give 276 mg (78%) of product(5) as an oil.

¹H NMR (DMSO, 400 MHz): δ 7.28-6.98 (6H, m), 6.82 (2H, d, J=8.68 Hz),3.99-3.81 (4H, m), 3.70 (3H, s), 3.24-3.15 (3H, m), 1.86-1.29 (14H, m),1.24 (6H, m). CI MS M+1=437. HPLC: RT=14.4 min. (Beckman 235328 C-18 5μm 4.6 mm×25 cm, eluted with a mixture of solvents consisting of (i)0.1% trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acidin acetonitrile, gradient profile 80:20 (i):(ii) to 10:90 (i):(ii) over23 minutes, flow rate 1.5 mL/minute, λ=214 nM).

Example 2

3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide

Step (a) Preparation of:3-[(E)-(2-nitrophenyl)methylidene]-1-benzofuran-2-one

Ortho-hydroxyphenylacetic acid (1.835 g, 0.012 mmol) was added to amixture of ortho-nitrobenzaldehyde (1.835 g, 0.012 mmol), aceticanhydride (10 mL) and triethylamine (1.7 mL, 0.012 mol), and then themixture was heated at 140° C. for 15 minutes. The mixture was allowed tocool to 80° C., at which point water (10 mL) was carefully added. Theprecipitated material was washed with methanol and dried to afford therequired product (7) (0.905 g, 28%). A further amount of product (1.523g) was recovered from the filtrate.

¹H NMR (DMSO, 400 MHz): δ 8.36 (1H, d, J=8.3 Hz), 8.15 (1H, s), 8.0-7.8(3H, m), 7.42 (1H, t, J=7.0 Hz), 7.31 (1H, d, J=7.5 Hz), 7.04 (2H, m).

APCI MS 267.Step (b) Preparation of:3-(2-hydroxyphenyl)-3,4-dihydro-2(1H)-quinolinone

To 3-[(E)-(2-nitrophenyl)methylidene]-1-benzofuran-2-one (7) (2.18 g,7.65 mmol) in methanol (70 mL) and THF (30 mL) was added Pd/C 20% (0.050g) and the mixture hydrogenated for 5 hours. Filtration andchromatography, eluant 30% EtOAc to 50% EtOAc in hexane, afforded therequired product (8) (0.913 g, 49%).

¹H NMR (DMSO, 300 MHz): δ 9.52 (1H, s), 7.15 (2H, m), 7.05 (1H, m), 6.97(1H, m), 6.89 (2H, d, J=7.3 Hz), 6.83 (1H, d, J=7.9 Hz), 6.67 (1H, t,J=7.3 Hz), 3.96 (1H, dd, J=10.4 Hz, 6.4 Hz), 3.19 (1H, dd, J=15.8 Hz,10.6 Hz), 2.99 (1H, dd, J=15.8 Hz, 10.6 Hz).

APCI MS 240.

Analysis C₁₅H₁₃N₁O₂: Required: C, 75.30; H, 5.48; N, 5.85. Found: C,74.95; H, 5.51; N, 5.61.Step (c) Preparation of:3-(5-bromo-2-hydroxyphenyl)-3,4-dihydro-2(1H)-quinolinone

To 3-(2-hydroxyphenyl)-3,4-dihydro-2(1H)quinolinone (8) (0.650 g, 2.72mmol) in carbon disulphide (10 mL) and methylene chloride (10 mL) wasslowly added (110 minutes) a solution of bromine (0.17 mL, 3.30 mmol) incarbon disulphide (5 mL). After 2 hours a precipitate had fully formedwhich was collected and washed with ether (2×10 mL). This afforded therequired product (9) (0.738 g, 85%).

¹H NMR (DMSO, 400 MHz): δ 10.29 (1H, s), 7.21 (2H, m), 7.16 (2H, m),6.91 (2H, m), 6.78 (1H, d, J=8.5 Hz), 3.93 (1H, dd, 3=12.0 Hz, 6.4 Hz),3.19 (1H, dd, J=15.4 Hz, 12.1 Hz), 2.97 (1H, dd, J=15.4 Hz, 6.3 Hz).

APCI MS 318/320.Step (d) Preparation of:3-[2-(benzyloxy)-5-bromophenyl]-3,4-dihydro-2-(1H)-quinolinone

To 3-(5-bromo-2-hydroxyphenyl)-3,4-dihydro-2(1H)-quinolinone (9) (3.16g, 9.94 mmol) in DMF (15 mL) was added cesium carbonate (5.2 g, 31 mmol)and then benzyl bromide (1.18 mL, 9.92 mmol). The mixture was stirred atroom temperature for 16 hours, diluted with ethylacetate (200 mL),washed with brine (100 mL), and then dried over MgSO₄. Chromatography,silica gel, eluant 20% EtOAc in hexane, affords the required product(10) (2.77 g, 68%).

¹H NMR (CDCl₃, 300 MHz): δ 8.40 (1H, brs), 7.30 (7H, m), 7.17 (1H, d,J=7.5 Hz), 7.11 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=6.3 Hz), 6.84 (1H, d,J=8.3 Hz), 6.78 (1H, d, J=7.9 Hz), 5.07 (2H, s), 4.09 (1H, dd, J=13.2Hz, 6.6 Hz), 3.38 (1H, dd, J=15.2 Hz, 13.2 Hz), 2.99 (1H, dd, J=15.8 Hz,6.6 Hz).

APCI MS 408/410.Step (e) Preparation of:4-(benzyloxy)-3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile

To 3-[2-(benzyloxy)-5-bromophenyl]-3,4-dihydro-2(1H)-quinolinone (10)(2.77 g, 6.79 mmol) in DMF (8 mL) was added copper (I) cyanide (2.7 g,30 mmol), and then the mixture was heated at an oil bath temperature of160° C. for 16 hours. The mixture was cooled, diluted with ethylacetate(200 mL), and washed with aqueous NH₄OH (2×°100 mL). After washing withbrine (2×100 mL) and drying over MgSO₄, the product was isolated bychromatography, silica gel eluant 30% ethylacetate to 50% ethylacetatein hexane, to afford (11) (1.077 g, 45%).

¹H NMR (DMSO, 300 MHz): δ 10.40 (1H, s), 7.77 (1H, dd, J=8.4 Hz, 2.0Hz), 7.69 (1H, d, J=2.2 Hz), 7.40-7.1 (8H, m), 6.89 (2H, m), 5.22 (2H,m), 4.04 (1H, dd, J=13.5 Hz, 6.6 Hz), 3.31 (1H, dd, J=15.7 Hz, 13.2 Hz),2.93 (1H, dd, J=15.7 Hz, 6.6 Hz).

APCI MS 355.Step (f) Preparation of:4-(benzyloxy)-3-[1-(5-bromopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarbonitrile

To4-(benzyloxy)-3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-benzenecarbonitrile(11) (0.270 g, 0.76 mmol) in DMF (3 mL) was added sodium hydride (60% inoil) (0.035 g, 0.9 mmol) and 1,5-dibromopentane (0.5 mL, 3.67 mmol), andthen the solution was stirred for 1 hour. The solution was diluted with1 N HCl (10 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried withmagnesium sulfate, filtered, and evaporated in vacuo. The residue waspurified on a silica gel column eluted with 20% ethyl acetate in hexane.The product (12) was isolated 0.230 g (60%) as an oil.

¹H NMR (CDCl₃, 300 MHz): δ 7.57 (1H, dd, J=8.6 Hz, 2.0 Hz), 7.42 (1H, d,J=2.0 Hz), 7.40-7.2 (6H, m), 7.13 (1H, d, J=6.4 Hz), 7.02 (3H, m), 5.15(2H,m), 4.04 (1H, dd, J=12.9 Hz, 5.9 Hz), 3.98 (2H, m), 3.39 (2H, t,J=6.6 Hz), 3.30 (1H, dd, J=15.4 Hz, 12.9 Hz), 2.96 (1H, dd, J=15.4 Hz,5.9 Hz), 1.88 (2H, m), 1.75-1.45 (4H, m).

APCI MS 503/505.Step (g) Preparation of: 3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)₄hydroxybenzenecarboximidamide

To (12)4-(benzyloxy)-3-[1-(5-bromopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarbonitrile(0.23 g, 0.457 mmol) was added cis-2,6-dimethylpiperidine (5 mL, 37.0mmol), and the solution was stirred at 70° C. for 48 hours. The mixturewas evaporated in vacuo. HPLC: RT=18.06 min. (Beckman 235328 C18 5 μm4.6 mm×25 cm, eluted with a mixture of solvents consisting of (i) 0.1%trifluoroacetic acid in water, and (ii) 0.1% trifluoroacetic acid inacetonitrile, gradient profile 80:20 (i):(ii) to 10:90 (i):(ii) over 23minutes, flow rate 1.5 mL/minute, λ=214 nM).

This mixture was dissolved in ethanol (10 mL) and treated with hydroxylamine hydrochloride (0.70 g, 10 mmol) and diisopropylethylamine (1.8 mL,10 mmol). After stirring for 24 hours, the reaction mixture wasevaporated and HPLC indicated the reaction was complete to afford4-(benzyloxy)-3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-hydroxybenzenecarboximidamideRT=12.37 min. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).

To this mixture was added trifluoroacetic acid (5 mL) andtrifluoroacetic anhydride (1 mL). After 2 hours the reaction mixture wasevaporated and HLPC indicated the reaction was complete RT=21.5 min.(Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with a mixture of solventsconsisting of (i) 0.1% trifluoroacetic acid in water, and (ii) 0.1%trifluoroacetic acid in acetonitrile, gradient profile 80:20 (i):(ii) to10:90 (i):(ii) over 23 minutes, flow rate 1.5 mL/minute, λ=214 nM).

The residue was redissolved in trifluoroacetic acid (10 mL) and treatedwith Pd/C 20% (0.05 g) and hydrogenated for 16 hours. The mixture wasfiltered through celite, treated with water 1 mL, and then evaporated.The residue was purified by preparative HPLC (Vydac 218TP 1022 C18,eluted with a mixture of solvents consisting of (i) 0.1% trifluoroaceticacid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile,gradient profile 95:5 (i):(ii) to 60:40 (i):(ii) over 90 minutes, flowrate 20 mL/minute, λ=214 nM), converted to the HCl salt by ion exchangechromatography, and then lyophilized to give 3-(1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)₄-hydroxybenzenecarboximidamidedihydrochloride (0.123 g, 50%) of product (13) as a powder.

CI MS M+1=463.

HPLC: RT=10.1 min. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).

¹H NMR (DMSO, 400 MHz): δ 10.89 (1H, s), 10.2 (1H, brs), 9.09 (2H, s),8.8 (1H, s), 7.62 (2H, m), 7.20 (3H, m), 7.0 (2H, in), 3.90 (3H, in),3.40 (1H in), 3.20 (2H, m), 3.00 (1H, m), 2.85 (2H, m), 1.80-1.2 (18H,in).

APCI MS 463.

Example 3

3-(1-5-[(2R,6S)2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide

Step (a) Preparation of:(E)-2-(3-hydroxyphenyl)-32-nitrophenyl)-2-propenoic acid

Into a mixture of o-nitrobenzaldehyde (19.22 g, 127 mmol) and3-hydroxyphenylacetic acid (19.30 g, 127 mmol) in acetic anhydride (87mL) was added triethylamine (17.5 mL, 126 mmol), and the reactionmixture was stirred and heated at reflux (150° C.) for 45 minutes. Thesolution was diluted with water (200 mL), cooled, diluted 2N NaOH (200mL), and washed with ether. The aqueous solution was then acidified with6N HCl to pH 3 and stirred for 3 hours. The solid was collected anddried under high vacuum at 45° C. to give 23.15 g (64%) of the requiredproduct (14).

¹H NMR (DMSO, 300 MHz): δ 8.09 (1H, m), 7.93 (1H, s), 7.48 (2H, in),_(—)7.00 (2H, m), 6.59 (1H, in), 6.48 (2H, m).

CI MS M+1=285.Step (b) Preparation of:3-(3-hydroxyphenyl)-3,4-dihydro-2(1H)quinolinone

To (E)-2-(3-hydroxyphenyl)-3-(2-nitrophenyl)-2-propenoic acid (14)(26.29 g, 92.0 mmol) in methanol (600 mL) was added 20% palladium oncarbon (1.5 g), and the mixture was hydrogenated at 45 PSI of H₂ at 30°C. for 3.5 hours. The mixture was filtered through celite and the filterpad washed with MeOH. The combined filtrate and washings wereconcentrated in vacuo. The product (15) was crystallized from methanolin water to give 17.95 g (82%) as a solid.

¹H NMR (DMSO, 400 MHz): δ 10.30 (1H, s), 9.31 (1H, s), 7.14 (2H, m),7.05 (1H, m), 6.90 (2H, m), 6.61 (3H, m), 3.70 (1H, m), 3.20-3.06 (2H,m).Step (c) Preparation of 3-(2-oxo-12,3,4-tetrahydro-3-quinolinyl)phenyltrifluoromethanesulfonate

To 3-(3-hydroxyphenyl)-3,4-dihydro-2(1H)-quinolinone (15) (3.01 g, 12.6mmol) in THF (40 mL) was added sodium hydride (0.55 g, 13.8 mmol), andthe solution was stirred at room temperature for 5 minutes. To thissolution was added N-phenyltrifluoromethanesulfonimide (4.92 g, 13.8mmol), and the solution was stirred at room temperature for 1 hour. Thesolution was cooled, diluted with water, and extracted with ethylacetate (3×200 mL). The combined organic extracts were washed with brine(2×100 mL), dried with magnesium sulfate, filtered, and evaporated invacuo. The residue was purified on a silica gel column eluted with 20%to 40% ethyl acetate in hexane. The product (16) was isolated 4.29 g(92%) as a yellow solid.

¹H NMR (CDCl₃, 400 MHz): δ 8.06 (1H, s), 7.40-7.15 (6H, bm), 7.00 (1H,m), 6.76 (1H, m), 3.87 (1H, m), 3.22 (2H, m).

CI MS M+1=372.Step (d) Preparation of: 3-(2-oxo-1,2,3,4-tetrahydro-3quinolinyl)benzenecarbonitrile

To 3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)phenyltrifluoromethanesulfonate (16) (0.410 g, 1.11 mmol) in DMF (5 mL) wereadded zinc cyanide (0.078 g, 0.690 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.128 g, 0.11 mmol). Thereaction mixture was stirred and heated at 100° C. for 1 hour. Thesolution was cooled, diluted with water (200 mL) and 2 M sulfuric acid(20 mL), and extracted with ethyl acetate (3×200 mL). The combinedorganic extracts were washed with brine (2×100 mL), dried with magnesiumsulfate, filtered, and evaporated in vacuo. The product (17) wascrystallized from hexane and ethyl acetate to give (0.222 g, 81%) as asolid.

¹H NMR (CDCl₃, 300 MHz): δ 8.23 (1H, s), 7.70-7.18 (6H, bm), 7.04 (1H,m), 6.81 (1H, m), 3.89 (1H, m), 3.24 (2H, in).

CI MS M+1=249.Step (e) Preparation of:3-[1-(5-bromopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarbonitrile

To 3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile (17)(2.76 g, 11.1 mmol) in DMF (15 mL) at 0° C. were added1,5-dibromopentane (10.22 g, 44.4 mmol) and sodium hydride (0.48 g, 12.0mmol), and the solution was stirred at this temperature for 3 hours. Thesolution was diluted with water and extracted with ethyl acetate (3×200mL). The combined organic extracts were washed with brine (2×100 mL),dried with magnesium sulfate, filtered, and evaporated in vacuo. Theresidue was purified on a silica gel column eluted with 20% ethylacetate in hexane. The product (18) was isolated 1.59 g (36%) as ayellow oil.

¹H NMR (CDCl₃, 300 MHz): δ 7.58-7.28 (5H, bm), 7.20 (1H, m), 7.05 (2H,m), 3.99 (2H, m), 3.85 (1H, m), 3.41 (2H, m), 3.19 (2H, m), 1.91 (2H,m), 1.70 (2H, m), 1.54 (2H, m).

CI MS M+1=397/399, M−1=395/396.Step (f) Preparation of:31-5-[(2R,6S)2,6-dimethyltetrahydro-t(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile

To3-[1-(5-bromopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]-benzenecarbonitrile(18) (1.59 g, 4.00 mmol) in DMF (3 mL) was addedcis-2,6-dimethylpiperidine (10 mL, 74 mmol). The solution was stirred at70° C. for 24 hours. The solution was cooled, diluted with water, andextracted with ethyl acetate (3 t 200 mL). The combined organic extractswere washed with saturated sodium bicarbonate (2×100 mL), washed withbrine (2×100 mL), dried with magnesium sulfate, filtered, evaporated invacuo, coevaporated with toluene, and dried under high vacuum to give(19) in quantitative yield as a yellow oil.

¹H NMR (CDCl₃, 300 MHz): δ 7.50-6.96 (8H, bm), 3.91 (2H, m), 3.80 (1H,in), 3.13 (2H, m), 2.67 (2H, bs), 2.36 (2H, bs), 1.66-1.15 (12H, bm),1.01 (6H, in).

HPLC: RT=14.25 min. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).Step (g) Preparation of:3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide

To3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile(19) (1.00 g, 2.33 mmol) in methanol (20 mL) were added hydroxylaminehydrochloride (0.40 g, 5.76 mmol) and diisopropylethylamine (0.40 mL,2.30 mmol). The solution was stirred at room temperature for 16 hours.The solvent was evaporated in vacuo, and the oil was dried under highvacuum to give (20) in quantitative yield.

HPLC: RT=9.22 min. (Beckman 235328 C18 5 μm 4.6 nm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).Step (h) Preparation of: 3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-[(2,2,2-trifluoroacetyl)oxy]benzenecarboximidamide

To3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide(20) (1.07 g, 23.1 mmol) was added trifluoroacetic anhydride (10 mL),and the solution was stirred at room temperature for 3 hours. Thesolvent was removed in vacuo to give (21) as a yellow oil inquantitative yield.

HPLC: RT=18.37 min. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).Step (i) Preparation of: 3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro 1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide

To3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-[(2,2,2-trifluoroacetyl)oxy]-benzenecarboximidamide(21) (1.27 g, 23.1 mmol) in trifluoroacetic acid (16 mL) was added 20%palladium on carbon (0.2 g), and the mixture was hydrogenated 33 PSI of112 at 23° C. for 3 hours. The mixture was filtered, and the filter padwashed with trifluoroacetic acid. The combined filtrate and washingswere evaporated in vacuo, and the residue was purified by preparativeHPLC (Vydac 218TP54C18, eluted with a mixture of solvents consisting of(i) 0.11% trifluoroacetic acid in water, and (ii) 0.11% trifluoroaceticacid in acetonitrile, gradient profile 95:5 (i):(ii) to 60:40 (i):(ii)over 90 minutes, flow rate mL/minute, 214 mm) and lyophilized to givethe TFA salt of (22) as an off-white solid. To the solid in acetonitrile(2 mL) and water (2 mL) was added Amberlite® IRA-400(CI) ion exchangeresin. The mixture was filtered through additional resin, and thefiltrate was lyophilized to give 619 mg (52%) of (22) as an off-whitesolid.

¹H NMR (DMSO, 400 MHz): 39.35 (1H, s), 9.07 (2H, s), 7.66 (2H, m), 7.49(2H, m), 7.21 (3H, m), 6.97 (1H, m), 3.95 (3H, m), 3.42 (4H, bs),3.35-2.86 (6H, bm), 1.75-1.26 (8H, bm), 1.20 (6H, m).

CI MS M+1=447.

HPLC: RT=9.65 min. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).

Example 4

3-[3-(aminomethyl)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone

3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile(19) (0.71 g, 16.5 mmol) was hydrogenated over Raney nickel (0.5 g) inmethanol (45 mL) and triethylamine (5 mL) for 4 hours at roomtemperature. The mixture was filtered and the filter pad washed withmethanol. The combined filtrate and washings were evaporated in vacuo,and the residue was purified by preparative HPLC (Vydac 218TP54 C18,eluted with a mixture of solvents consisting of (i) 0.1% trifluoroaceticacid in water, and (ii) 0.1% trifluoroacetic acid in acetonitrile,gradient profile 95:5 (i):(ii) to 60:40 (i):(ii) over 90 minutes, flowrate 20 mL/minute, λ=214 nm) and lyophilized to give the TFA salt of(23) as an off-white oily solid. To the oily solid in acetonitrile (2mL) and water (2 mL) was added Amberlite® IRA-400(CI) ion exchangeresin. The mixture was filtered through additional resin, and thefiltrate was lyophilized to give 380 mg (45%) of (23) as an off-whitesolid.

¹H NMR (DMSO, 400 MHz): δ 8.38 (2H, s), 7.35-7.10 (7H, m), 6.95 (1H, m),3.92 (4H, m), 3.83 (1H, m), 3.36 (4H, s), 3.23-2.86 (6H, bm), 1.75-1.30(8H, bm), 1.21 (6H, m).

CI MS M+1=434.

HPLC: RT=9.56. (Beckman 235328 C18 5 μm 4.6 mm×25 cm, eluted with amixture of solvents consisting of (i) 0.1% trifluoroacetic acid inwater, and (ii) 0.1% trifluoroacetic acid in acetonitrile, gradientprofile 80:20 (i):(ii) to 10:90 (i):(ii) over 23 minutes, flow rate 1.5mL/minute, λ=214 nM).

The invention compounds have demonstrated factor Xa inhibitory activityin the standard assays commonly employed by those skilled in the art.

Determination of Factor Xa IC₅₀ and K_(i) Constants

The ability of compounds to act as inhibitors of human factor Xacatalytic activity is assessed by determination of that concentration oftest substance that inhibits by 50% (IC₅₀) the ability of human factorXa to cleave the chromogenic substrate S2765(N-CBz-D-Arg-L-Gly-L-Arg-p-nitroanilide. 2HCl, DiaPharma). Typically,145 μL human factor Xa (1 nM final, Enzyme Research Laboratories) in 10mM HEPES, 150 mM NaCl, 0.1% BSA, pH 7.4 (HBSA buffer) and 5 μL of testsubstance in DMSO (2% final) are incubated for 60 minutes at roomtemperature. Following preheating to 37° C. for 5 minutes, to thismixture is added 1100 μL of S2765 in HBSA buffer. The velocity of S2765hydrolysis is determined at 37° C. by measuring the initial rate ofchange of the optical density at OD₄₀₅ nM every 10 seconds for 5 minutesusing a ThermoMax®D Kinetic Microplate Reader.

For K_(i) determinations the assay conditions were essentially the sameas above except for the following. The concentration of factor Xa was 50μM, and that of the substrate, in this case a fluorogenic S2765 (i.e.,S2765 with AMC tag instead of pNA, California Peptide Research), wasover the range of 10 to 500 μM. The test compound and substrate in HBSAbuffer were incubated as above, and the reaction was initiated withenzyme-buffer. The data (steady-state velocity at various concentrationsof the substrate and the inhibitors) of the competitive inhibition wasanalyzed using the methods described by Segel (Enzyme Kinetics, WileyInterscience Publications, 1993). A non-linear regression program,Kaleidograph and/or Microsoft Excel, was used to estimate the kineticparameters (K_(m) V_(max) and K_(i)) by use of Michaelis-Menten andreciprocal Dixon plot fits.

Determination of Thrombin IC₅₀ and K_(i) Constants

The ability of compounds to act as inhibitors of human thrombincatalytic activity is assessed by determination of that concentration oftest substance that inhibits by 50% (IC₅₀) the ability of human thrombinto cleave the chromogenic substrate Chromozym TH(Tosyl-Gly-Pro-Arg-pNA*Ac, Boehringer Mannheim). Typically, 145 μL humanthrombin (0.75 nM, Enzyme Research Laboratories) in a HPB buffer (10 mMHEPES, 100 mM NaCl, 0.05% BSA, 0.1% PEG-8000, pH 7.4) and 5 μL of testsubstance in DMSO (2% final) are incubated for 60 minutes at roomtemperature. Following preheating to 37° C. for 5 minutes, to thismixture is added 100 μL of Chromozym TH in HPB buffer. The velocity ofChromozym TH hydrolysis is determined at 37° C. by measuring the initialrate of change of the optical density at OD₄₀₅ nM every 10 seconds for 5minutes using a ThermoMax® Kinetic Microplate Reader.

For K_(i) determinations the assay conditions were essentially the sameas the aforementioned except for the following. The concentration ofthrombin used was 50 μM, and that of a fluorogenic Chromozym TH (i.e.,Chromozym TH with AMC instead of pNA tag, Novabiochem) was over therange of 1 to 40 μM. The test compound and substrate in HPB buffer wereincubated as above, and the reaction was initiated with enzyme-bufferand run at 24° C. Kinetic analysis was performed as for factor Xa K_(i)determinations.

Determination of Trypsin IC₅₀ and K_(i) Constants

The ability of compounds to act as inhibitors of human trypsin catalyticactivity is assessed by determination of that concentration of testsubstance that inhibits by 50% (IC₅₀) the ability of human trypsin tocleave the chromogenic substrate S2222(N-Bz-L-Ile-L-Glu-L-Gly-L-Arg-p-nitroanilide. HCl, DiaPharma).Typically, 145 μL human trypsin (0.5 nM final) in 10 mM HEPES, 150 mMNaCl, 0.1% BSA, and 5 μL of the test substance in DMSO (2% final) areincubated for 60 minutes at room temperature. Following preheating to37° C. for 5 minutes, to this mixture is added 100 μL of S2222 in HBSAbuffer (100 μM final), and the velocity of S2222 hydrolysis isdetermined at 37° C. by measuring the optical density at OD₄₀₅ nM every10 seconds over 5 minutes using a ThermoMax® Kinetic Microplate Reader.

For K_(i) determinations, the assay conditions were essentially the sameas the aforementioned except that the reaction was initiated withenzyme-buffer and run at 24° C. using a substrate range of 10 to 500 μM.Kinetic analysis was performed as for factor Xa K_(i) determinations.

Determination of Tissue Factor/Factor VIIa IC₅₀

The ability of compounds to act as inhibitors of the catalytic activityof human tissue factor/factor VIIa complex is assessed by determinationof that concentration of test substance that inhibits by 50% (IC₅₀ theability of a complex of human recombinant tissue factor/factor VIIa tocleave the chromogenic substrate Spectrozyme VIIa (CH₃SO₂-D-CHA-Arg-pNA*AcOH, American Diagnostica). Typically, 50 μL humanfactor VIIa (Enzyme Research Laboratories) is incubated for 10 minutesas a 1:1 mixture (5 nM final each) with 95 μL recombinant human tissuefactor (American Diagnostica) in a modified HBSA buffer (10 mM Hepes, 5mM CaCl₂, 0.1% BSA, pH 8.0). Then, 5 μL of the test substance in DMSO(2% final) is added and incubated for 60 minutes at room temperature.Following preheating to 37° C. for 5 minutes, to this mixture is added100 μL of Spectrozyme VIIa (500 μM final) in modified HBSA, and thevelocity of Spectrozyme VIIa hydrolysis is determined at 37° C. bymeasuring the optical density at an OD₄₀₅ nM every 10 seconds over 5minutes using a ThermoMax® Kinetic Microplate Reader.

In Vitro Assay for Human Prothrombinase

This assay demonstrates the ability of test compounds of the inventionto inhibit the human prothrombinase (PTase) complex (typicallycomprising of human factor Va, human factor Xa, Ca²⁺, and phospholipidmoiety) and thereby, the subsequent cleavage of prothrombin to yieldthrombin. For determination of IC₅′ (PTase) of the compounds of theinvention, PTase activity was expressed by thrombin activity.

PTase reaction was performed in 100 μL of mixture containing PTase (20μM) PCPS (Avanti Polar Lipids following a procedure modified fromBarenholz et al., Biochemistry, 1977;16:2806-2810) in a 30:70 ratio, 2.5nM human factor Va (Enzyme Research Laboratories) and 2.5 μM humanfactor Xa (Enzyme Research Laboratories) in modified HEPES buffer (10 mMHepes, 150 mM NaCl, 0.1% PEG-8000, 0.05% BSA, 2.5 mM CaCl₂, pH 7.4), 3μM human prothrombin (Enzyme Research Laboratories) and variedconcentrations of the test compounds (1 nM to 100 μM in DMSO, 2% final).Reaction was started by co-incubating PTase with test compound for 60minutes at room temperature, followed by addition of prothrombin for 6minutes at room temperature. Next, the reaction was quenched by theaddition of 100 μL of 20 mM EDTA. Activity of the thrombin (product) isthen measured in the presence of 50 μL S2238 (250 μM final,H-D-Phe-Pip-Arg-pNA*Ac, DiaPharma) as substrate by measuring the changeat 37° C. in OD₄₀₅ nM for 5 minutes at 10-second intervals using aThermoMax® Kinetic Microplate Reader.

Determination of Prothrombin Time (PT)

Rat, rabbit, dog and human blood (typically 1.8 mL) was collected andadded to a sodium citrate solution (3.8%) to afford a 1:10 dilution.After centrifugation (2000 g for 10 minutes), the blood plasma wasstored at −70° C. to 0° C. Conventional prothrombin time tests werecarried out in the presence of various concentrations of test compoundand the concentration of test compound required to double the clottingtime determined. Typically, the test compound (50 μL volume of varyingconcentrations 0.1 μM to 1000 μM) and blood plasma (100 μL volume) wereincubated at 37° C. for 10 minutes and then tissue thromboplastin,typically Neoplastine from American Bioproducts with calcium, was added.Fibrin formation and the time required for a clot to form weredetermined using an automated ST4 Clot Detection System in duplicate.

In an ex-vivo modification of this assay, drug was administeredintravenously or orally to a group of rats or rabbits. At various timesblood samples were collected, and the PT coagulation assay as describedabove were performed.

Arterio-Venous Shunt Stasis Antithrombotic Model

In vivo measurements of antithrombotic activity were performed accordingto the procedure of Vogel et al., Thromb. Res., 1989;54:399-410.Briefly, the vena cava was exposed, collateral veins were ligated, andsutures were loosely located around the inferior vena cava. Thesesutures were tightened after drug administration to induce stasis withinthe ligated portion of the vena cava. After an appropriate time, thethrombus was isolated and weighed. The effect of varying drugconcentrations administered intravenously or orally on thrombus massreflected antithrombotic activity.

Alternatively, and according to the procedure of Smith et al., Br. J.Pharmacol., 1982;77:29-38, the left jugular and right carotid arterywere exposed and cannulated. A shunt, which contains silk threads orpreweighed cotton, is then inserted which connects the two cannulatedvessels. Once drug has been administered, the shunt is closed, and thethrombus that forms on the foreign surface in the shunt is removed aftera period of time. Clot weight then reflects antithrombotic activity.

Arterial Thrombosis Model

FeCl₃ Induced Carotid Arterial Injury Model

The FeCl₃ induced injury to the carotid artery in rats was inducedaccording to the method described by Kurz K. D., Main R. W., Sandusky G.E., Thrombosis Research, 1990;60:269-280 and Schumacher W. A. et al., J.Pharmacology and Experimental Therapeutics, 1993;267: 1237-1242.

Male, Sprague-Dawley rats (375-410 g) were anesthetized with urethane(1500 mg\kg·ip). Animals were laid on a 37° C. heating pad. The carotidartery was exposed through a midline cervical incision. Careful bluntdissection was used to isolate the vessel from the carotid sheath. Usingforceps, the artery was lifted to provide sufficient clearance to inserttwo small pieces of polyethylene tubing (PE-205) underneath it. Atemperature probe (Physitemp MT23/3) was placed between one of thepieces of tubing and the artery. Injury was induced by topicalapplication on the carotid artery above the temperature probe of a smalldisc (3 mm diameter) of Whatman No. 1 filter paper previously dipped ina 35% solution of FeCl₃. The incision area was covered with aluminumfoil in order to protect the FeCl₃ from degradation by light. The vesseltemperature was monitored for 60 minutes after application of FeCl₃ asan indication of blood flow. Vessel temperature changes were recorded ona thermister (Cole-Palmer Model 0853341).

The time between the FeCl₃ application and the time at which the vesseltemperature decreased abruptly (>2.4° C.) was recorded as the time toocclusion of the vessel. The fold shift in mean occlusion time (MOT),therefore, refers to the time to occlusion in drug-treated animaldivided by control time to occlusion. Inhibitor compounds were given asan intravenous bolus (0.75 mg/kg) followed immediately by an intravenousinfusion (50 μg/kg/min via femoral vein).

Typically, the compounds of the invention show 50% inhibition of factorXa proteolytic activity on a synthetic substrate in concentrationsranging from 50 μM to 1 nM.

Thrombin Trypsin Xa Structure Name IC₅₀ μM IC₅₀ μM IC₅₀ μM

3-(1-5-[(2R,6S)-2,6- dimethyltetrahydro- 1(2H)- pyridinyl]pentyl-2-oxo-1,2,3,4- tetrahydro-3- quinolinyl)-4- hydroxybenzenecarboximidamide (Example 2) 1.14 0.562 0.02

The foregoing biological test has been used to establish the compoundsof this invention are useful for preventing and treating thromboticdisorders, for example, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism,first or recurrent myocardial infarction, unstable angina, and cerebralinfarction, stroke, and atherosclerosis.

The compounds of the present invention can be administered alone or incombination with one or more therapeutic agents. These include, forexample, other anticoagulant, antiplatelet, or platelet inhibitoryagents which include non-steroidal anti-inflammatory agents such asaspirin, ibuprofen, naproxen sodium, indomethacin, piroxicam andticlopidine, thrombin inhibitors such as argatroban, efegatran,inogatran, factor VIIa inhibitors, thrombolytic or fibrinolytic agentssuch as tissue plasminogen activator, urokinase or streptokinase, and GPIIIb-IIa antagonists.

The compounds are thus well-suited to formulation for convenientadministration to mammals for the prevention and treatment of suchdisorders, The following examples farther illustrate typicalformulations provided by the invention.

Formulation 1 Ingredient Amount Compound of Formulas I-IV 200 mg Sodiumbenzoate 5 mg Isotonic saline 1000 mL

The above ingredients are mixed and dissolved in the saline for IVadministration to a human suffering from, for example, arterialthrombosis.

Formulation 2 Ingredient Amount Compound of Formulas I-IV 100 mgCellulose, microcrystalline 400 mg Stearic acid 5 mg Silicon dioxide 10mg Sugar, confectionery 50 mg

The ingredients are blended to uniformity and pressed into a tablet thatis well-suited for oral administration to a human for preventing, forexample, cerebral infarction.

Formulation 3 Ingredient Amount Compound of Formulas I-IV 200 mg Starch,dried 250 mg Magnesium stearate 10 mg

The ingredients are combined and milled to afford material suitable forfilling hard gelatin capsules administered to humans suffering from, forexample, venous thrombosis.

Formulation 4 Amount % wt/wt Compound of Formulas I-IV 1 Polyethyleneglycol 1000 74.5 Polyethylene glycol 4000 24.5

The ingredients are combined via melting and then poured into moldscontaining 2.5 g total weight.

Formulation 5 Ingredient Amount % wt/wt Compound of Formulas I-IV 0.1%Propellant 11/12 98.9% Oleic acid 1%

The ingredients are dispersed in oleic acid with the propellant. Themixture is added to an aerosol container fitted with a metering device.

1. A compound according to Formula I

or a stereoisomers or pharmaceutically acceptable salts, esters, oramides thereof, wherein: A is selected from CH₂, CH, C(alkyl); B isselected from H, alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl,heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, eachoptionally substituted with R₁ and R₂; D is selected from H, alkyl,cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl,arylalkyl, heterocycle, heterocycloalkyl, each optionally substitutedwith R₁ and R₂; E is absent or selected from O, S, NH; F is selectedfrom N or NCH₂; G is selected from alkyl, alkyl interrupted by one ormore heteroatoms, cycloalkyl, cycloalkyl interrupted by one or moreheteroatoms; J is heterocycle optionally substituted with R₁ and R₂; Kis absent or selected from an alkyl, alkyl interrupted by one or moreheteroatoms, cycloalkyl interrupted by one or more heteroatoms,cycloalkylalkyl interrupted by one or more heteroatoms, each optionallysubstituted with R₁ and R₂; L is selected from H, chlorine, fluorine,bromine, iodine, OH, O(alkyl), alkyl, fluoroalkyl, NO₂, SH,S(O)_(n)(alkyl), SO₃H, SO₃alkyl, C(═O)heteroaryl, C(═O)heteroarylalkyl,C(═O)OH, NC(═O)alkyl, NC(═O)aryl, NC(═O)cycloalkyl,NC(═O)cycloalkylalkyl, NC(═O) alkylaryl, R₁, R₂; R₁ is selected from H,C(═NH)NHNH₂, alkylC(═NH)NHNH₂, C(═NH)NHOH, alkylC(═NH)NHOH, NHC(═NH)NH₂,alkylNHC(═NH)NR₂, C(═S)NH₂, alkylC(═S)NH₂, C(═NH)alkyl,alkylC(═NH)alkyl, C(═NR₃)N(R₄)(R₅), alkylC(═NR₃)N(R₄)(R₅); R₂ isselected from H, chlorine, fluorine, bromine, iodine, OH, Oalkyl,NC(═O)alkyl, NC(═O)aryl, NC(═O)cycloalkyl, NC(═O)alkylaryl, C(═O)alkyl,C(═O)cycloalkyl. C(═O)cycloalkyl, C(═O)aryl, C(═O)alkyl, C(═O)heteroaryland C(═O)heteroarylalkyl, NO₂, SH, S(O)_(n)(C₁₋₁₀alkyl), SO₃H, SO₃alkyl,CHO, C(═O)OH, alkyl, C(═NH)alkyl, C(═NH)NHNH₂, alkylC(═NH)NHNH₂,C(═NH)NHOH, alkylC(═NH)NHOH, NHC(═NH)NH₂, alkylNHC(═NH)NHNH₂, C(═S)NH₂,alkylC(═S)NH₂, alkylC(—NH)alkyl, C(═NR₃)N(R₄)(R₅),alkylC(═NR₃)N(R₄)(R₅); R₃, R₄, and R₅ are a hydrogen atom, alkyl grouphaving 1 to 4 carbon atoms optionally interrupted by a heteroatom, or R₄and R₅ arc bonded to form —(CH₂)_(p)—W—(CH₂)_(q)-, wherein p and q arean integer of 2 or 3, a certain position on the methylene chain isunsubstituted or substituted by an alkyl group having 1 to 4 carbonatoms, W is a direct bond, —CH₂—, —O—, —N(R₆)—, or —S(O)₂— wherein R₆ isH or alkyl, and r is 0 or 1 or 2; n is selected from 0, 1, 2; X₁ is C;X₂ is C; X₃ is C; X₄ is C; and --- represents an optional additionalbond.
 2. A compound according to claim 1 according to Formula II

or a stereoisomers or pharmaceutically acceptable salts, esters, oramides thereof, wherein B, G, J, K, L, and --- are as defined above. 3.A compound according to Formula III

or a stereoisomer or pharmaceutically acceptable salts, esters, or amidethereof, wherein X, Y, R₇, R₉, and --- are as follows: X is selectedfrom (CH₂)₅, (CH₂)₄, (CH₂)₆, CH₂C(═O)NHCH₂CH₂, CH₂CH₂NHC(═O)CH₂,(CH₂)₂NH(CH₂)₂, (CH₂)₂O(CH₂), C₆H₄, CH₂C₆, C₆H₄CH₂, C₆H₁₀, CH₂C₆H₁₀,C₅H₈, CH₂C₅H₈, C₅H₈CH₂, and CH₂CH═CHCH₂CH₂; Y is selected from2,6-dimethylpiperidinyl, piperidinyl,2,2,6,6-tetramethyl-piperidinyl-4-one, (2-carboxy)piperidinyl,(3-carboxy)piperidinyl, (4-carboxy)piperidinyl, 3,5-dimethylpiperidinyl,(4-hydroxy)piperidinyl, (2-imino)piperidinyl, piperidin-4-one-yl,(2-dimethylaminomethyl)-piperidinyl, (4-dimethylamino)-piperidinyl,(4-sulphonyloxy)piperidinyl, (2-phenyl)piperidinyl,2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy)pyrrolidinyl,(3-N-acetyl-N-methyl)pyrrolidinyl, (3-amino)pyrrolidinyl,(2,5-bis-methoxymethyl)-pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl,2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino, diethylamino,methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl,2,5-dimethyl-1H-1-imidazolyl, morpholinyl, 2,6-dimethylmorpholinyl,piperazinyl, 2,6-dimethylpiperazinyl, 1H-pyrazolyl,tetrahydro-1H-pyrazolyl, 2,5-dimethyltetrahydro-1H-1-pyrazolyl, and1,2,3,4-tetrahydro-2-oxo-3-phenyl-1-quinolinyl; R₇ is selected from(3-amidino)phenyl, phenyl, 4-methoxyphenyl, 4-(amidino)phenyl,3-(aminocarbonyl)phenyl, 3(methoxycarbonyl)phenyl, (3-hydroxy)phenyl,[3-hydroxyamino(imino)methyl]-phenyl, [3-hydrazino(imino)methyl]-phenyl(3-aminomethyl)phenyl, (3-amino)phenyl, (3-methylamino)phenyl,(3-dimethylamino)phenyl, (5-amidino-2-hydroxy)phenyl,(1-amidino)piperid-3-yl, (1-amidino)pyrrolid-3-yl,(5-amidino)thien-2-yl, (5-amidino)furan-2-yl,(5-amidino)-1,3-oxazol-2-yl, (2-amidino)-1,3-oxazol-5-yl,1H-pyrazol-5-yl, tetrahydro-1H-pyrazol-3-yl,(1-amidino)tetrahydro-1H-pyrazol-3-yl, (2-amidino)-1H-imidazol-4-yl,(2-amino)-1H-imidazol-4-yl, (5-amidino)-1H-imidazol-2-yl,(5-amino)-1H-imidazol-2-yl, pyridin-3-yl, (4-amino)pyridin-3-yl,(4-dimethylamino)pyridin-3-yl, (6-amino)pyridin-2-yl,(6-amidino)pyridin-2-yl, (2-amino)pyridin-4-yl, (2-amidino)pyridin-4-yl,(2-amidino)pyrimid-4-yl, (2-amino)pyrimidin-4-yl,(4-amidino)pyrimid-2-yl, (4-amino)pyridin-2-yl (6-amidino)pyrazin-2-yl,(6-amino)pyrazin-2-yl, (4-amidino)-1,3,5-triazin-2-yl,(4-amino)-1,3,5-triazin-2-yl, (3-amidino)1,2,4-triazin-5-yl,(3-amino)-1,2,4-pyridin-5-yl, (3-amidino)benzyl, (3-amino)benzyl,(3-aminomethyl)benzyl, (1-amidino)piperid-3-ylmethyl,(1-amidino)pyrrolid-3-ylmethyl, (5-amidino)thien-2-ylmethyl,(5-amidino)furan-2-ylmethyl, (5-amidino)oxazol-2-ylmethyl,(2-amidino)imidazol-5-ylmethyl, (5-amidino)imidazol-2-ylmethyl,(6-amidino)pyridin-2-ylmethyl, (6-amidino)pyridin-2-ylmethyl,(2-amidino)pyridin-4-ylmethyl, (2-amino)pyrimidin-4-ylmethyl,(4-amidino)pyrimidin-2-ylmethyl, (4-amino)pyrimidin-2-ylmethyl,(6-amidino)pyrazin-2-ylmethyl, (6-amino)pyrazin-2-ylmethyl,3-aminocyclohexyl, 3-amidinocyclohexyl, 3-aminocyclohexylmethyl,3-amidinocyclohexylmethyl, 3-aminocyclopentyl, 3-amidinocyclopentyl,3-aminocyclopentylmethyl, and 3-amidinocyclopentylmethyl; and R₈ isselected from H, Cl, F, SH, SMe, CF₃, CH₃, CO₂H, CO₂Me, CN, C(═NH)NH₂,C(═NH)NHOH, C(═O)NH₂, C(═O)NH₂, CH₂OH, CH₂NH₂, NO₂, OH, OMe, OCH₂Ph,OCH₂CO₂H, O(CH₂)₂CO₂H, O(CH₂)₃CO₂H, NHCH₂CO₂H, NH(CH₂)₂CO₂H,NH(CH₂)₃CO₂H, OCH₂CH₂OH, OCH₂(1H-tetrazol-5-yl), NH₂, NHButyl, NMe₂,NHCH₂Ph, NHC(═O)Me, NHC(═O)c-Hexyl, NHC(═O)CH₂c-Hexyl, NHC(═O)Ph,NHC(═O)CH₂Ph, NHS(═O)₂Me, NHS(═O)₂c-Hexyl, NHS(═O)₂CH₂c-Hexyl,NHS(═O)₂Ph, and NHS(═O)₂CH₂Ph; and --- represents an optional additionalend.
 4. A compound according to Formula IV

or a stereoisomers or pharmaceutically acceptable salts, esters, oramides thereof, wherein X, Y, R₇, R₈, and --- are as follows: X isselected from (CH₂)₅, (CH₂)₄, (CH₂)₆, CH₂C(═O)NHCH₂CH₂, CH₂CH₂NHC(O)CH₂,(CH₂)₂NH(CH₂)₂, (CH₂)₂O(CH₂)₂, C₆H₄, CH₂C₆H₄, C₆H₄CH₂, C₆H₁₀, CH₂C₆H₁₀,C₆H₁₀CH₂, C₅H₈, CH₂C₅H₈, C₅H₈CH₂, and CH₂CH═CHCH₂CH₂; Y is selected from2,6-dimethylpiperidinyl, piperidinyl,2,2,6,6-tetramethyl-piperidinyl-4-one, (2-carboxy)piperidinyl(3-carboxy)piperidinyl, (4-carboxy)piperidinyl, 3,5-dimethylpiperidinyl,(4-hydroxy)piperidinyl, (2-imino)piperidinyl, piperidin-4-one-yl,(2-dimethylaminomethyl)-piperidinyl, (4 dimethylamino)-piperidinyl,(4-sulphonyloxy)-piperidinyl, (2-phenyl)piperidinyl,2,5-dimethylpyrrolidinyl, pyrrolidinyl, (2-carboxy)pyrrolidinyl,(3-N-acetyl-N-methyl)pyrrolidinyl, (3-amino)pyrrolidinyl,(2,5-bis-methoxymethyl)-pyrrolidinyl, 2-hydroxymethyl-pyrrolidinyl,2-hydroxymethyl-5-methyl-pyrrolidinyl, diisopropylamino, diethylamino,methylamino, 1-methyl-4,5-dihydro-1H-imidazol-2-yl,2,5-dimethyl-1H-1-imidazolyl, morpholinyl, 2,6-dimethylmorpholinyl,piperazinyl, 2,6-dimethylpiperazinyl 1H-pyrazolyl,tetrahydro-1H-pyrazolyl, and 2,5-dimethyltetrahydro-1H-1-pyrazolyl; R₇is selected from (3-amidino)phenyl, (3-hydroxy)phenyl,[3-hydroxy]amino(imino)methyl-phenyl, [3-hydrazino(imino)methyl)-phenyl,(3-aminomethyl)phenyl (3-methylamino)phenyl, (3-dimethylamino)phenyl,(5-amidino-2-hydroxy)phenyl, (1-amidino)piperid-3-yl,(1-amidino)pyrrolid-3-yl, (5-amidino)thien-2-yl, (5-amidino)film-2-yl,(5-amidino)-1,3-oxazol-2-yl, (2-amidino)-1,3-oxazol-5-yl,1H-pyrazol-5-yl, tetrahydro-1H-pyrazol-3-yl,(1-amidino)tetrahydro-1H-pyrazol-3-yl, (2-amidino)-1H-imidazol-4-yl,(2-amidino)-1H-imidazol-4-yl, (5-amidino)-1H-imidazol-2-yl,(5-amino)-1H-imidazol-2-yl, pyridin-3-yl, (4-amino)pyridin-3-yl(4-dimethylamino)pyridin-3-yl, (6-amino)pyridin-2-yl,(6-amidino)pyridin-2-yl, (2-amino)pyridinyl, (2-amidino)pyridin-4-yl,(2-amidino)pyridine-4-yl, (2-amino)pyrimidin-4-yl,(4-amidino)pyrimid-2-yl (4-amino)pyrimidin-2-yl, (6-amino)pyrazin-2-yl,(6-amidino)pyrazin-2-yl, (4-amidino)-1,3,5-triazin-2-yl,(4-amino)-1,3,5-triazin-2-yl, (3-amidino)-1,2,4-triazin-5-yl,(3-amino)-1,2,4-triazin-5-yl, (3 amidino)benzyl, (3-amino)benzyl,(3-aminomethyl)benzyl, (1-amidino)piperid-3-ylmethyl,(1-amidino)pyrrolid-3-ylmethyl, (5-amidino)thien-2-ylmethyl,(5-amidino)furan-2-ylmethyl, (5-amidino)oxazol-2-ylmethyl,(2-amidino)imidazol-5-ylmethyl, (5-amidino)imidazol-2-ylmethyl,(6-amidino)pyridin-2-ylmethyl, (6-amino)pyridin-2-ylmethyl,(2-amidino)pyrimidin-4-ylmethyl, (2-amino)pyrimidin-4-ylmethyl,(4-amidino)pyrimidin-2-ylmethyl, (4-amino)pyrimidin-2-ylmethyl,(6-amidino)pyrazin-2-ylmethyl, (6-amino)pyrazin-2-ylmethyl,3-aminocyclohexyl, 3-amidinocyclohexyl, 3-aminocyclohexylmethyl,3-amidinocyclohexylmethyl, 3-aminocyclopentyl 3-amidinocyclopentyl3-aminocyclopentylmethyl, and 3-amidinocyclopentylmethyl; and R₈ isselected from H, Cl, F, SH, SMe, CF₃, CH₃, CO₂H, CO₂Me, CN, C(═NH)NH₂,C(═NH)NHOH, C(═NH)NHNH₂, C(═O)NH₂, CH₂OH, CH₂NH₂, NO₂, OH, OMe, OCH₂Ph,OCH₂CO₂H, O(CH₂)₂CO₂H, O(CH₂)₃CO₂H, NHCH₂CO₂H, NH(CH₂)₂CO₂H,NH(CH₂)₃CO₂H, OCH₂CH₂OH, OCH₂(1H-tetrazol-5-yl), NH₂, NHButyl, NMe₂,NHPh, NHCH₂Ph, NHC(═O)Me, NHC(═O)c-Hexyl, NHC(═O)CH₂c-Hexyl, NHC(═O)Ph,NHC(═O)CH₂Ph, NHS(═O)₂Me, NHS(═O)₂c-Hexyl, NHS(═O)₂CH₂c-Hexyl,NHS(═O)₂P, and NHS(═O)₂CH₂Ph; and --- represents an optional additionalbond.
 5. A compound according to claim 4 where X is (CH₂)₅.
 6. Acompound according to claim 4 where Y is 2,6-dimethylpiperidinyl.
 7. Acompound according to claim 4 where R₇ is (2-hydroxy-5-amidino)phenyl.8. A compound according to claim 4 wherein R₈ is H.
 9. A compoundaccording to claim 4 where X is (CH₂)₅, Y is 2,6-dimethylpiperidinyl andR₈ is H.
 10. A compound according to claim 4 where X is (CH₂)₅, Y is2,5-dimethylpyrrolidinyl and R₈ is H.
 11. A compound which is:3-(1-5-[(2)-2,6-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-33-hydroxyphenyl)-2(1H)-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl)pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-N-hydroxybenzenecarboxamide;3-(1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidohydrazide;3-[3-(Aminomethyl)phenyl]-1-5-[(2R,6S)-2,6dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-(3-Aminophenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-[3-(methylamino)phenyl]-2(1H)-quinolinone;3-[3-Dimethylamino)phenyl]-1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo1,2-dihydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)tetrahydro-[(2H)-pyridinecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl-1-pyrrolidinecarboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolyl)-2-thiophenecarboximidamide;5-(1-S-(2R,6S)2-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)₂-furancarboximidamide;2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3-oxazole-5-carboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3-oxazole-2-carboximidamide;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-1H-pyrazol-3-yl)-2(1H)-quinolinone;1-5-(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-tetrahydro-1H-pyrazol-3-yl-2(1-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1-pyrazolidinecarboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3quinolinyl)-1H-imidazole-2-carboximidamide;3(2-Amino-1H-imidazol-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2(1H)-quinolinone;2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-pentyl-2-oxo-1,2-dihydro-3-quinolinyl)1H-imidazole-5-carboximidamide;3-(5-Amino-1H-imidazol-2-yl)-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-pyridinyl)-2(1H)quinolinone;3-(6-Amino-3-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-[6(Dimethylamino)-3-pyridinyl]-1-5-1(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-(6-Amino-2-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)quinolinone;(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyridinecarboximidamide;(2-Amino-4-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2(1H)-quinolinone;4-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-pyridinecarboximidamide;4-(1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1-(2H)-pyridinyl]pentyl-2-oxo1,2-dihydro-3-quinolinyl)2-pyridinecarboximidamide;3-(2-Amino-4-pyridyl)-1-5-[(2R₆S)-2,6-methyltetrahydro-(2H)-pyridinyl]pentyl-2(1H)-quinolinone;2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-4-pyrimidinecarboximidamide;3-(4-Amino-2-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(21)-pyridinyl]pentyl-2(1H)-quinolinone;6-(1-5-[((2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl-pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-2-triazine-3-carboximidamide;3-(6-Amino-2-pyrazinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,3,5-triazine-2-carboximidamide;3-(4-Amino-1,3,5-triazin-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-1,2,4-triazine-3-carboximidamide;3-(3-Amino-1,2,4-triazine-5-yl)-1-5-(2R,6S)-2,6-dimethyltetrahydro-1-(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]benzenecarboximidamide;3-(3-Aminobenzyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)quinolinone;3-[3-(Aminomethyl)benzyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1-pyrrolidinecarboximidamide;5-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-thiophenecarboximidamide;5-[(1-5-[(2R,6S)-2,6Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3quinolinyl)methyl)-2-furancarboximidamide;2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1,3-oxazole-5-carboximidamide;5-[(1-5-[(2R₁₆S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1H-imidazole-2-carboximidamide;2-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-1H-imidazole-5-carboximidamide;6-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyridinecarboximidamide;3-[(6-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;4-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyrimidinecarboximidamide;3-[(2-Amino-4-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;2-[(1-5-((2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinone)methyl]4-pyrimidinecarboximidamide;3-[(4-Amino-2-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;6-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]-2-pyrazinecarboxamide;3-[(6-Amino-2-pyrazinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1-(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-(3-Aminocyclohexyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)cyclohexanecarboximidamide;3-[(3-Aminocyclohexyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl]cyclohexanecarboximidamide;3-(3-Aminocyclopentyl)-1-S-(2R,6S)2,6-dimethyltetrahydro-1-(2H)-pyridinyl]pentyl-2(1H)-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)cyclopentanecarboximidamide;3-[(3-Aminocyclopentyl)methyl]-1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)methyl)cyclopentanecarboximidamide;3-(1-4[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]butyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-6[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;2-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]-N-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2)-pyridinyl]ethylacetamide;3-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]-N-[(2R,6S)-2,6-Dimethyltetrahydro-1(2)pyridinyl]methylpropanamide;3-1-[2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]ethoxyethyl)-2-oxo-1,2dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-4[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]phenyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-4-(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-2-oxo1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl)cyclohexylmethyl)-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)₂-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-(4-((2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-(3-[(2R,6S)2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-(3-[(2R,6S)2,6-]Dimethyltetrahydro-[(2H)-pyridinyl]methylcyclopentyl)-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-(E5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-[2-Oxo1-(5-piperidinopentyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;3-2-oxo-1-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-[(2H)-quinolinyl]pentyl-2-piperidinecarboxylicacid;1-5-3-3[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-3-piperidinecarboxylicacid;1-5-3-3[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-3-piperidinecarboxylicacid;3-1-[5-(3,5-Dimethylpiperidino)pentyl]-2-oxo-2-dihydro-3-quinolinylbenzenecarboxamide;3-1-[5-(4-Hydroxypiperidino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboxamide;3-1-[5-(2-Iminopiperidino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboxamide;3-2-Oxo-1-[5-(4-oxopiperidino)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboxamide;3-[1-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboxamide;3(1-5-[4-(Diethylamino)piperidino]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboxamide;1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-4-piperidinesulfonicacid;3-2-Oxo-1-[5-(2-phenylpiperidino)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-2-Oxo-1-[5-(1-pyrrolidinyl)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-pyrrolidinecarboxylicacid;N-(1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyltetrahydro-1H-pyrrol-3-yl)N-methylacetamide;3-1-[5-(3-Amino-1-pyrrolidinyl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-(1-5-[2,5-bis(Methoxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-S-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-1-[5-(Diisopropylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(Diethylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(Methylamino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-[1-(5-Morpholinopentyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;3-1-[5-(3,5-Dimethylmorpholino)pentyl-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-[2-oxo-1-(5-Piperazinopentyl)-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,6-Dimethylpiperazino)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-2-Oxo-1-5-(1H-pyrazol-1-yl)pentyl]-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-[2-Oxo-1-(5-tetrahydro-1H-pyrazol-1-yl)pentyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;3-1-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-(7-Chloro-1-5-[(2R,6S)-2,6-dimethyltetrahydro1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-(2R,6S)2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-fluoro-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-sulfanyl-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-7-(methylsulfonyl)2-oxo-1,2-dihydro-3-quinolyl]benzenecarboximidamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)pyridinyl]pentyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1( )pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxylic acid; Methyl3-3-[amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxylate;3-(7-Cyano-1-5-[(2R,6S)-2,6dimethyltetrahydro-(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-3-(Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinecarboximidamide;3-3-[Amino(imino)methyl]phenyl-1-5-(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-N-hydroxy-2-oxo-1,2-dihydro-7-quinolinecarboximidamide;3-1-5-((2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]phenyl-7-hydrazino(imino)methyl]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboxamide;3-3-(Amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinecarboxamide;3-{[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(hydroxymethyl)-2-oxo-1,2-dihydro-3-quinolinyl]benzenecarboximidamide;3-(7-(Aminomethyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-nitro-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(21)pyridinyl]pentyl-7-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-1,5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methoxy-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-(Benzyloxy)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]aceticacid,3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(S)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]propanoicacid;4-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]butanoicacid;2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]aceticacid;3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]propanoicacid;4-((3-3-[Amino(imino)methyl]phenyl-1-S-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]butanoicacid;3-[1-5-[(2H)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-(2-hydroxyethoxy)-2-oxo-1,2dihydro-3-quinolinyl)benzenecarboximidamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(21H)-pyridinyl]pentyl-2-oxo-7-(1H-1,2,3,4-tetrazol-5-ylmethoxy)-1,2-dihydroquinolinyl]benzenecarboximidamide;3-(7-Amino-1-5-(2R,6S)-2,6-dimethyltetrahydro-[(2-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-Butylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-(imino)methyl-1-5-(2R,6S)-2,6-dimethyltetrahydro-1(21H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-Anilino1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-(Benzylamino)-1-S-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro 3-quinolinyl) benzenecarboxamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)acetamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)cyclohexanecarboxamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-pyridinyl]pentyl-2-oxo-1,2dihydro-7-quinolinyl)-2-cyclohexylacetamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)benzenecarboximidamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-((2R,6S)-2,6-dimethyltetrahydro-[(2)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-phenylacetamide;3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-[(methylsulfonyl)amino]-2-oxo-1,2-dihydro-3-quinolinylbenzenecarboximidamide;3-(7-[(Cyclohexylsulfonyl)amino)-1-5-((2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl)phenyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(7-((Cyclohexylmethyl)sulfonyl]amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-7-[(phenylsulfonyl)amino]-1,2dihydro-3-quinolinylbenzenecarboximidamide;3-(7-[(Benzylsulfonyl)amino]-1-5-C(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)2,6-Dimethyltetrahydro-1(28)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-hydroxyphenyl)3,4-dihydro-2(1H)-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)N-hydroxybenzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidohydrazide;3-[3-(Aminomethyl)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinylpentyl-3,4-dihydro-2(1H)-quinolinone;3-(3-Aminophenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-[3-(methylamino)phenyl]-3,4-dihydro-2(1H)-quinolinone;3-[3-(Dimethylamino)phenyl]-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)tetrahydro-1(2-pyrrolidinecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1-pyrrolidinecarboximidamide;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-thiophenecarboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-furancarboximidamide;2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)1,3-oxazole-carboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,3-oxazole-2-carboximidamide;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(1H-pyrazol-3-yl)-3,4-dihydro-2(1H)quinolinone;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-3-tetrahydro-1H-pyrazol-3-yl-3,4-dihydro-2(1H)-quinolinone;3-(1-5-((2R,6S)-2,6-Dimethyltetrahydro 1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1-pyrazolidinecarboximidamide;5-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)1H-imidazole-2-carboximidamide;3-(2-Amino-1H-imidazol-5-yl)-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;2-(15-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo1,2,3,4-tetrahydro-3-quinolinyl) 1H-imidazole-5-carboximidamide;3-(5-Amino-1H-imidazol-2-yl)-1-5-[(2R,6S)-2,6Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-3-(3-pyridinyl)-3,4-dihydro-2(1H)-quinolinone;3-(6-Amino-3-pyridinyl)-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;3-(6-(Dimethylamino)-3-pyridinyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;3-(6-Amino-2-pyridinyl)-1-5-[2R,6S)-2,6Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1}1)quinolinone;6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyridinecarboximidamide;3-(2-Amino-4-pyridinyl)-1-S-(2R,6S)-2,6-dimethyltetrahydro-[(M-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyridinecarboximidamide;(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)₂-pyrimidinecarboximidamide;3-Amino-4-pyrimidinyl)-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;2-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-4-pyrimidinecarboximidamide;3-(4-Amino-2-pyrimidinyl)-1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;6-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H₁)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-2-pyrazinecarboximidamide;3-(6-Amino-2-pyrazinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl-pentyl-3,4-dihydro-(2H)-quinolinone;4-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,3,5-triazine-2-carboximidamide;3-(4-Amino-1,3,5-triazin-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1)quinolinone;6-(1-5-(1-5-((2R,6S)-2,6-Dimethyltetrahydro-[(2>pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-1,2,4-triazine-3-carboximidamide;3-(3-Amino-1,2,4-triazin-5-yl)-1-5-[(2R,6S)-2,&dimethyltetrahydro 1(2H)-pyridinyl)pentyl-3,4-dihydro-2(1H)quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-(2H)-pyridinyl]pentyl-2-oxo1,2,3,4-tetrahydro-3-quinolinyl)methyl]benzenecarboximidamide;3-(3-Aminobenzyl)-1-5-((2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;3-[3-(Aminomethyl)benzyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]tetrahydro(2H)-pyridinecarboximidamide;3-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1-pyrrolidinecarboximidamide;5-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-thiophenecarboximidamide;5-[(1-S-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-furancarboximidamide;2-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1,3-oxazole-5-carboximidamide;5-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1H-imidazole-2-carboximidamide;2-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-1H-imidazole-5-carboximidamide;6-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1H-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-pyrazinecarboximidamide;3-[(6-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1quinolinone;4-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]-2-pyrazinecarboximidamide;3-[(2-Amino-4-pyrimidinyl)methyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)quinolinone;2-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]4-pyrazinecarboximidamide;3-[(4-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;6-[(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3quinolinyl)methyl]-2-pyrazinecarboximidamide;3-[(6-Amino-2-pyrazinyl)methyl]-1-5-[(2R,6S)-2.6dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;3-(3-Aminocyclohexyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-yl-3,4-dihydro-2(1H)-quinolinone;3-(1-S—C(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)cyclohexanecarboximidamide;3-[(3-Aminocyclohexyl)methyl]-1-5-[(2R,6S)2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl-3,4-dihydro-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]cyclohexanecarboximidamide;3-(3-Aminocyclopentyl)-1-S-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]cyclohexanecarboximidamide;3-[(3-Aminocyclopentyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3,4-dihydro-2(1H)-quinolinone;3-[(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)methyl]cyclopentanecarboximidamide;3-(1-4[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]butyl-2-oxo-1,2,3,4tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;2-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;3-[3-3-(Amino(imino)methyl]phenyl-2-oxo-1(2H)quinolinyl]-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]methylpropanamide;3-1-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[14-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-4-[(2R,6S)2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-4(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)₂-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-(4-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]methylcyclohexyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-3(2R,6S)-2,6-Dimethyltetrahydro-1(pyridinyl]cyclopentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]cyclopentylmethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolyl]benzenecarboximidamide;3-[1-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[2-Oxo-1-(5-piperidinopentyl)-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-2-Oxo-1-1-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-[(2H)-quinolinyl]pentyl-2-piperidinecarboxylicacid;1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-[(2H)-quinolinyl]pentyl-3-piperidinecarboxylicacid;1-5-3-3[Amino(imino)methyl]phenyl-2-oxo-[(2H)-quinolinyl]pentyl-4-piperidinecarboxylicacid;3-1-[5-(3,5-Dimethylpiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(4-Hydroxypiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2-Iminopiperidino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-2-Oxo-1-[5-(4-oxopiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(1-5-[4-(Dimethylamino)piperidino)pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;1-5-[3-3-[amino(imino)methyl]phenyl-2-oxo1(2H)-quinolinyl]pentyl-4-piperidinesulfonic acid;3-2-Oxo-1-[5-(2-phenylpiperidino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,5-Dimethyl-1-pyrolidinyl)pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-2-oxo-1-[5-(1-pyrrolidinyl)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;1-5-[3-3-[no(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-2-pyrrolidinecarboxylicacid;N-(−5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinolinyl]pentyl-tetrahydro-1H-pyrrol-3-yl)-N-methylacetamide;3-1[5-(3-Amino-1-pyrrolidinyl]pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-(1-S-[2,5-bis(Methoxymethyl)-1-pyrrolidinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-2-oxo 1,2,3,4-tetrahydro3-quinolinyl)benzenecarboximidamide;3-(1-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-1-[5-(Diisopropylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[S-(Diethylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(Methylamino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-[1-(5-Morpholinopentyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-1-[5-(3,5-Dimethylmorpholino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-[2-oxo-11-5-piperazino)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-1-[5-(2,6-Dimethylpiperazino)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-2-oxo-1-[5-(1H-pyrazol-1-yl)pentyl]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-[2-Oxo-1-(5-tetrahydro-H-pyrazol-1-yl)pentyl]-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-1-(5-(2,5-dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-(7-Chloro-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-fluoro-2-oxo1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-sulfanyl-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-[(2H)-pyridinyl]pentyl-7-(methylsulfanyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetra-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-methyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxylicacid; methyl3-3-(Amino(imino)methyl]phenyl-1-S-[(2R,6S)-2,6-dimethyltetrahydro1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxylate;3-(7-Cyano-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-3-[Amino(imino)methyl-3-phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboximidamide;3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-[(21)-pyridinyl]pentyl-N-hydroxy-2-oxo1,2,3,4-tetrahydro-7-quinolinecarboximidamide;3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)pyridinyl]pentyl-7-[hydrazino(imino)methyl]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-7-quinolinecarboxamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(pyridinyl]pentyl-7-(hydroxymethyl)-2-oxo-1,2,3,4-tetrahydro-3-quinolyl]benzenecarboximidamide;3-(7-(Aminomethyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-nitro-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-[(2R,6S)-2,6-Dimethyltetrahydro-1(2-pyridinyl]pentyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-((2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pyridinyl-7-methoxy-2-oxo-1,2,3-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7-(Benzyloxy)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;2-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-quinolinyl)oxy]aceticacid;3-[(3-3-[Amino(imino)methyl]phenyl--5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]propanoicacid;4-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)oxy]butanoicacid;2-[(3-3-(Amino(imino)methyl]phenyl-1-5-[(2R₆S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]aceticacid;3-[(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(pyridinyl-pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]propanoicacid;4-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)amino]butanoicacid;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(pyridinyl]pentyl-7-(2-hydroxyethoxy)-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-[1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2-pyridinyl]pentyl-2-oxo-7-(1H-1,2,3,4-tetrahydro-1-5-ylmethoxy)-1,2,3,4-tetrahydro-3-quinolinyl]benzenecarboximidamide;3-(7-Amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7-(Butylamino)-1-5-(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7-(Dimethylamino)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7-Anilino-1-5-t(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7(Benzylamino)-1-5-[(2R,6S)-2,6dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;N3-3-[Amino(no)methyl]phenyl-1-5-[(2R,6S)-2,6,4-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo1,2-dihydro-7-quinolinyl)acetamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)cyclohexanecarboxamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolinyl)-2-cyclohexylacetamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-quinolinyl)benzenecarboxamide;N-(3-3-[Amino(imino)methyl]phenyl-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-7-quinolyl)-2-phenylacetamide;3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7-[(methylsulfonyl)amino]-2-oxo-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;3-(7-[(Cyclohexylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;3-(7-[(Cyclohexylmethyl)sulfonyl]amino-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide;1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-(4-methoxy-phenyl)-3,4-dihydro-1H-quinolin-2-one;3-1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-7-[(phenylsulfonyl)amino]-1,2,3,4-tetrahydro-3-quinolinylbenzenecarboximidamide;or3-(7-[(Benzylsulfonyl)amino]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarboximidamide.12. A compound which is:3-(1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)benzenecarboximidamide;3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-N-hydroxybenzenecarboximidamide;3-[3-(Aminomethyl)phenyl]3-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinolinone;or3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide.13. A compound which is:3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)-4-hydroxybenzenecarboximid amide; or3-(1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2-oxo-1,2-dihydro-3-quinolinyl)-4-hydroxybenzenecarboximidamide.14. A method for the treatment of thrombotic disorders in a mammalcomprising administering to said mammal an effective amount of acompound according to claim
 1. 15. A method according to claim 14,wherein said disorder is venous thrombosis.
 16. A method according toclaim 14, wherein said disorder is arterial thrombosis.
 17. A methodaccording to claim 14, wherein said disorder is pulmonary embolism. 18.A method according to claim 14, wherein said disorder is myocardialinfarction.
 19. A method according to claim 14, wherein said disorder iscerebral infarction.
 20. A method according to claim 14, wherein saiddisorder is restenosis.
 21. A method according to claim 14, wherein saiddisorder is cancer.
 22. A method according to claim 14, wherein saiddisorder is angina.
 23. A method according to claim 14, wherein saiddisorder is diabetes.
 24. A method according to claim 14, wherein saiddisorder is heart failure.
 25. A method according to claim 14, whereinsaid disorder is arterial fibrillation.
 26. A pharmaceutical formulationcomprising a compound of claim 1 admixed with a carrier, diluent, orexcipient.
 27. A pharmaceutical formulation comprising a compound ofclaim 2 together with a carrier, diluent, or excipient.
 28. Apharmaceutical formulation comprising a compound of claim 11 togetherwith a carrier, diluent, or excipient.
 29. A method for inhibitingserine proteases comprising administering to a mammal an effectiveamount of serine protease inhibitor of claim
 1. 30. A method accordingto claim 29, wherein said serine protease is factor Xa.